bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA28: Towards a therapy for Angelman syndrome by targeting a long noncoding RNA to active UBE3A
Authors: Meng Linyan , Ward Amanda J. , Bennett C. Frank , Beaudet Arthur , Rigo Frank
Published: May 2016

Angelman syndrome (AS) is a single gene disorder characterized by intellectual disability, developmental delay, behavioral uniqueness, speech impairment, seizures, and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition increased paternal Ube3a expression. Despite a clear understanding of the disease-causing event in AS and the potential to harness the intact paternal allele to correct disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for AS by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an AS mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, for the first time we developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.

Citation Format: Linyan Meng, Amanda J. Ward, C. Frank Bennett, Arthur Beaudet, Frank Rigo. Towards a therapy for Angelman syndrome by targeting a long noncoding RNA to active UBE3A. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA28.
Abstract PR06: The enhancer landscape involves a core noncoding RNA protein interaction network for C-MYC expression
Authors: Zhang Fan , Song Won-min , Li SiDe , Ajay Vashisht , Aguilo Francesca , Bagchi Anindya , Wohlschlegel James A. , Zhang Bin , Walsh Martin
Published: May 2016

Many long non-coding RNAs (lncRNAs) that regulate the capacity of cells to undergo oncogenic transformation still remain unknown. However, their involvement in chromatin organization has been an emerging principle in cancer epigenomics. This recent concept has been documented through recent studies of the gene -poor chromosomal region 8q24 surrounding the C-MYC locus to understand the mechanisms enforcing or suppressing tumor cell growth from C-MYC transcription levels. In light of such examples informing us of the DNA elements and the epigenomic composition that become integrated into molecular programs that regulate C-MYC, some lncRNAs in non-genic regions are considered landmarks that enforce chromatin state changes to accommodate C-MYC expression. Here, we use an integrative genomic and proteomic approach to gain insight of how an endogenously tagged lncRNA PCAT-1 utilizes the chromatin and biochemical context to shape C-MYC locus topology to promote tumor cell growth, survival and fitness. Our results now find that WDR74 forms an integrative hub involving recognition of the m7G cap of lncRNA transcripts along with, RNMT, RAM, BRD4, β catenin, EZH2 that assist in a program that enforce C-MYC transcription and stabilize transcripts through utilizing a comprehensive mixture of cis-acting DNA elements, lncRNAs and trans functioning transcriptional and RNA capping complexes for prostate tumor cell growth. Our results now place the lncRNA PCAT-1 and the novel interacting WD40 repeat protein WDR74 at the axis along with β catenin, BRD4 and EZH2, and additional RBPs as a non -canonical chromatin complex to shape the chromosomal topology that benefit prostate cancer cell growth.

Citation Format: Fan Zhang, Won-min Song, SiDe Li, Vashisht Ajay, Francesca Aguilo, Anindya Bagchi, James A. Wohlschlegel, Bin Zhang, Martin Walsh. The enhancer landscape involves a core noncoding RNA protein interaction network for C-MYC expression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr PR06.
Abstract OT2-01-04: E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group
Authors: Connolly R , Zhao F , Miller K , Tevaarwerk A , Wagner L , Lee M , Murray J , Gray R , Piekarz R , Zujewski JA , Sparano J
Published: May 2016

Background:

A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression after a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), and overall survival (OS). Entinostat has been designated a Breakthrough Therapy by the FDA.

Methods:

E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer with prior disease progression on a NSAI (n=600). Patients receive exemestane 25mg po daily and entinostat/placebo 5mg po every week. Eligibility: Postmenopausal women and men, ECOG 0-1, locally advanced/metastatic invasive adenocarcinoma of the breast: ER/PR-positive, HER2-negative, measurable or non-measurable (20% cap) disease. Disease progression after NSAI use in the metastatic setting OR relapse while on or within ≤ 12 months of end of adjuvant NSAI therapy.

Statistics: Both PFS (central review) and OS are primary endpoints, and the study is designed to show an improvement in either PFS or OS. Secondary endpoints include: Safety and tolerability, objective response rate, changes in lysine acetylation status in peripheral blood mononuclear cells, patient-reported symptom burden and treatment toxicities, adherence. One-sided type 1 error 0.025 split between two hypotheses tests: 0.001 for PFS test and 0.024 for OS. PFS is tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS 4.1 to 7.1 months); OS is tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS 22 to 29.3 months).

E2112 was activated in March 2014 and accrual is anticipated to complete in 40 months.

Citation Format: Connolly R, Zhao F, Miller K, Tevaarwerk A, Wagner L, Lee M, Murray J, Gray R, Piekarz R, Zujewski JA, Sparano J. E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-04.
Abstract P2-06-05: LINC00478: A novel tumor suppressor in breast cancer
Authors: Gökmen-Polar Y , Zavodszky M , Chen X , Gu X , Kodira C , Badve S
Published: May 2016

Background:

LncRNAs may play a role in cancer and serve as new potential targets for improving cancer diagnosis, prognosis or treatment. Long intergenic non-protein coding RNA 478 (LINC00478), the miR99a-let-7c cluster host gene, has been shown to be downregulated in estrogen-independent ER-positive (ER+) breast cancer cells. However, its expression in breast tumors and its significance in recurrence has not been well characterized.

Methods:

The clinical relevance of LINC00478 in ER+ breast tumors was first determined by analysis of the expression levels in MiTranscriptome database (RNAseq-based), which contains ∼8000 most differentially expressed lncRNAs for each cancer and/or tissue type. Additionally, the expression of LINC00478 mRNA was determined in a) a cohort of matched pairs of primary and (nodal) metastatic tumors (n=18) (RNA-seq) and b) a cohort of 60 paraffin-embedded ER-positive, node-negative breast carcinomas with Oncotype DX recurrence scores (QRT-PCR).

Results:

LINC00478 was significantly downregulated in patients with ER-positive tumors compared to uninvolved normal breast tissue. In RNA-seq analysis, metastatic tumors had significant low expression as compared to matched primary tumors (FC: -2.2 fold-down; P=0.0027). Quantitative RT-PCR analysis showed that LINC00478 expression was significantly lower in ER+ node-negative patients with Oncotype DX high recurrence score when compared with low recurrence score patients (FC: -4.14-fold down; P=0.02).

Conclusion:

We document for the first time that LINC00478 functions as a tumor suppressor in ER-positive breast cancer. Its loss is associated with tumor progression and recurrence/metastasis. Novel strategies that focus on re-expression of LINC00478 might be useful for targeting breast cancer and preventing the metastases.

Citation Format: Gökmen-Polar Y, Zavodszky M, Chen X, Gu X, Kodira C, Badve S. LINC00478: A novel tumor suppressor in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-06-05.
Abstract P4-04-03: Targeting of phosphatidylserine by monoclonal antibodies augments the activity of immune checkpoint inhibitor PD-1/PD-L1 therapy in murine breast tumors
Authors: Gray M , Gong J , Nguyen V , Hutchins J , Freimark B
Published: May 2016

Phosphatidylserine (PS) is a phospholipid that typically resides in the inner leaflet of the plasma membrane in many types of cells, including both tumor and tumor associated endothelial cells. Conditions that cause cellular stress, including those that occur from oxygen radicals, hypoxia, irradiation, and chemotherapy, cause a dramatic shift in PS localization. This change in localization results in PS shifting to the outer plasma membrane, allowing its recognition by components of the tumor microenvironment. Recognition of PS promotes an immunosuppressive environment that encourages tumor growth, in part by promoting the recruitment of myeloid derived suppressor cells, immature dendritic cells, and M2-like macrophages, in addition to inducing production of anti-inflammatory cytokines. Currently the chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapies to treat patients with solid tumors in multiple late-stage clinical trials, where it is believe to help augment the efficacy of chemotherapeutics by blockade of PS-mediated immunosuppression and triggering an Fc-FcR mediated pro-inflammatory response in the tumor microenvironment. While the results with PS targeting therapies with chemotherapeutics are encouraging, the effectiveness of PS targeting therapies in conjunction with therapies towards immune checkpoint regulators remains largely unknown. To better understand the role of PS-targeting in breast cancers, and its effectiveness when used in combination with checkpoint inhibitors, immune competent mice harboring either EMT-6 or E0771 breast tumors were utilized. Treatments comprised PS targeting antibodies and an anti-PD1 antibody (to interrupt the PD-1/PD-L1 signaling axis) either alone or in combination with each other, and the effect on tumor growth and immune suppression determined. In both models, which showed differential sensitivity to therapy, the inclusion of PS targeting antibodies with the checkpoint blocker antibody had a significantly greater anti-tumor response than either single agent alone.

Citation Format: Gray M, Gong J, Nguyen V, Hutchins J, Freimark B. Targeting of phosphatidylserine by monoclonal antibodies augments the activity of immune checkpoint inhibitor PD-1/PD-L1 therapy in murine breast tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-03.
Abstract PD1-07: Mammographic density and SNPs add to Tyrer-Cuzick and Gail model breast cancer risk in a UK screening cohort
Authors: Evans DG , Astley SM , Brentnall A , Howell A , Cuzick J
Published: May 2016

Background: The predicting risk of cancer at screening study (PROCAS) in Manchester UK is a prospective study of breast cancer risk estimation. This article considers whether mammographic density and SNPs in PROCAS may help refine breast cancer risk estimation using the Gail (BCRAT) and Tyrer-Cuzick (TC, or IBIS) models, based on incident and prevalent breast cancers identified between two three-yearly screening rounds.

Methods: Mammographic density was measured at entry as a percentage using the average visual assessment from two trained readers. Tyrer-Cuzick and Gail risks were based on a questionnaire completed at the same time. The contribution of density to risk models was assessed after adjustment for age and body mass index (BMI) using odds ratios (ORs) and profile likelihood confidence intervals (CIs). A secondary analysis compared cancer pathology characteristics using a two-sided Wilcoxon test. Eighteen breast cancer risk variants (SNP18) were assessed with a polygenic risk score (PRS) alongside TC and density in a subset of 8870 women with 341 prospective cancers.

Results: Analysis included 50628 women of routine screening age (47-73 yrs), recruited between Aug 2009 and Jul 2014. 697 had a breast cancer diagnosed after enrolment. Median follow-up was 3.2 years. Visually assessed percentage breast density (inter-quartile range odds ratio (IQR OR) 1.48 (95%CI 1.34-1.63)) was a slightly stronger univariate risk factor than TC (IQR OR 1.36 (1.25-1.48)) or Gail (IQR OR 1.22 (1.12-1.33)). It continued to add information after allowing for TC (IQR OR 1.47 (1.33-1.62)) or Gail (IQR OR 1.45 (1.32-1.60)). 36472/50628 (72%) women had less than 3.5% 10-yr risk from the TC model and breast density combined. Women with dense breasts were more likely to have a higher stage breast cancer (P <.001). SNP18 showed a 2 fold relative breast cancer risk between the top and bottom quintile. Using a combined analysis of SNP18, TC and density there was a 5.6 fold risk between those identified at NICE defined high risk compared to low risk.

Conclusion: Breast density and SNPs when combined with the TC or Gail risk model identify a larger number of high risk women at screening, and it is associated with higher stage of disease. Approximately 70% of women are identified with a combined TC and density risk assessment of less than 3.5% 10-yr risk (average or less than average risk), for whom three-yearly screening might be effective. SNP18 adds further precision and addition of further newly identified SNPs is likely to add greater discrimination.

Citation Format: Evans DG, Astley SM, Brentnall A, Howell A, Cuzick J. Mammographic density and SNPs add to Tyrer-Cuzick and Gail model breast cancer risk in a UK screening cohort. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD1-07.
Abstract S4-07: Tamoxifen resistance driven by the DNA cytosine deaminase APOBEC3B in recurrent estrogen receptor positive breast cancer
Authors: Harris R , Law E , Sieuwerts A , LaPara K , Leonard B , Starrett G , Temiz NA , Sweep F , Span P , Foekens J , Martens J , Yee D
Published: May 2016

Recent studies have implicated the DNA cytosine deaminase APOBEC3B as a major source of mutation in breast cancer. APOBEC3B explains a large proportion of both dispersed and clustered cytosine mutations, the latter of which are also called kataegis. APOBEC3B expression levels correlate with poor outcomes for patients with estrogen receptor positive breast cancer. While targeted therapies, such as tamoxifen, are available to treat these tumors, secondary drug resistance often develops. Here we suppressed endogenous APOBEC3B in the estrogen receptor positive breast cell line MCF-7L with shRNA. Lowered levels of APOBEC3B did not affect in vitro growth or sensitivity to estradiol. In a xenograft model of tamoxifen therapy, suppression of APOBEC3B associated with prolonged responses to tamoxifen (p<0.05). Furthermore, APOBEC3B over-expression did not affect in vitro cell growth but accelerated the development of tamoxifen-resistant tumors in vivo. In addition, we studied two separate cohorts of 285 breast cancer patients who received first line treatment with tamoxifen for recurrent disease. High APOBEC3B expression levels measured in the primary tumor associated significantly with unfavorable progression free survival in multivariate analysis that included the traditional predictive factors (age, dominant relapse site, disease-free interval, estrogen receptor and progesterone receptor, and adjuvant chemotherapy; HR=1.67, p=0.0001). The median period of progression free survival was 7.5 months for patients with APOBEC3B high primary tumors and 13.3 months for those with APOBEC3B low tumors (p<0.0.0001). These studies demonstrate that APOBEC3B drives resistance to endocrine treatment with tamoxifen in recurrent disease.

Citation Format: Harris R, Law E, Sieuwerts A, LaPara K, Leonard B, Starrett G, Temiz NA, Sweep F, Span P, Foekens J, Martens J, Yee D. Tamoxifen resistance driven by the DNA cytosine deaminase APOBEC3B in recurrent estrogen receptor positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S4-07.
Abstract A13: African American breast cancer survivors in the digital age
Authors: Leader Amy , DiCarlo Melissa , Bradley Patricia , Hagerty Sarah , Barsevick Andrea
Published: May 2016

The information needs of breast cancer survivors are varied and complex. How African American breast cancer survivors (AABCS) access cancer-related information and the extent to which they find the information helpful is not well understood. We conducted a statewide survey with 297 female AABCS and led 8 in-depth focus groups with 60 female AABCS to understand where AABCS look for health information and their preferred format of materials. We were also interested in the extent to which AABCS used social media services to look for information or to bolster their supportive networks. The average age of those who completed the survey was 57.5 years, and almost all (95%) received surgical treatment for their breast cancer; 77% received radiotherapy and 53% chemotherapy. Almost all (95%) reported at least one co-morbid health condition such as hypertension or diabetes; 22% reported five or more co-morbid conditions. The majority of AABCS (85%) reported using informational books or brochures, followed by in-person talks or lectures by experts (56%). AABCS also found these two formats to be the most helpful. Not surprisingly, most AABCS preferred to receive information in written form (59%) or in-person (60%). Although most of the AABCS in our sample (70%) had access to the Internet in their home and many (61%) were on Facebook, the majority (63%) reported that they are not members of social networking sites such as Twitter or Google Plus, and few (<10%) reported using these platforms for sharing their cancer-related experiences, connecting to other survivors, or accessing health-related information. The discussions of AABCSs in the focus groups echo these findings with stories of difficulty finding information tailored to their needs and frustration that too many resources are only available online. The results from this mixed-methods study suggest that while many organizations have moved their cancer information online, there are segments of the population, such as AABCS, who continue to rely on and prefer print materials and in-person formats to manage their health care needs. Organizations should aim to increase AABCS' familiarity and ease of accessing online health information, as many AABCS have access to the Internet yet do not perceive online materials or social networking services to be as helpful for addressing their needs.

Citation Format: Amy Leader, Melissa DiCarlo, Patricia Bradley, Sarah Hagerty, Andrea Barsevick. African American breast cancer survivors in the digital age. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A13.
Abstract A29: Efficacy study of a group-based promotora intervention to increase cervical cancer screening among immigrant Latina women
Authors: Luque John S. , Tarasenko Yelena N. , Alfonso Moya L. , Reyes-Garcia Claudia , Rebing Laura , Ferris Daron G.
Published: May 2016

Background: This study evaluates the feasibility and efficacy of a promotora-led, Spanish-language educational group session on cervical cancer screening (Pap tests), self-efficacy (belief in ability to schedule and complete a Pap test), and knowledge among Latina immigrants compared to a control condition.

Methods: The group-based promotora intervention, Salud es Vida, consisted of a toolkit of materials which includes a curriculum guide, a brochure, a flipchart, a short animated video, and in-class activities. Data from baseline and follow-up/post-intervention surveys were used to assess differences in obtaining a Pap test using the Chi-square test of independence and in self-efficacy and knowledge scores using t-tests.

Results: We recruited 38 women to the intervention and 52 women to the control who were due for Pap test screening. After an average of 8 months until the follow-up assessment, twelve (32%) intervention participants received the Pap test and 10 (19%) control participants received the Pap test (p = .178). At follow-up, the intervention group participants had higher total cervical cancer knowledge and higher self-efficacy scores, adjusting for the posttest scores, respectively (p's < .05).

Conclusions: The findings from this feasibility study using a group intervention approach suggest intervention efficacy for increasing cervical cancer knowledge and self-efficacy; however, these secondary outcomes alone were not sufficient to increase cervical cancer screening rates in this Latina immigrant population during the study period.

Citation Format: John S. Luque, Yelena N. Tarasenko, Moya L. Alfonso, Claudia Reyes-Garcia, Laura Rebing, Daron G. Ferris. Efficacy study of a group-based promotora intervention to increase cervical cancer screening among immigrant Latina women. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A29.
Abstract A70: Is the availability of fast food restaurants and tobacco outlets near schools in 97 U.S. counties associated with school sociodemographic characteristics?
Authors: D’Angelo Heather , Ammerman Alice , Gordon-Larsen Penny , Linnan Laura , Lytle Leslie , Ribisl Kurt M.
Published: May 2016

Background: Fast food and tobacco product availability near schools might influence youth diet and tobacco use, and greater availability near racially diverse or lower income schools may contribute to racial/ethnic and socioeconomic disparities in cancer risk. However, no national studies have examined the availability of both fast food restaurants and retail tobacco outlets near schools in the United States (US) in association with school sociodemographic characteristics.

Methods: Fast food restaurants and tobacco outlets were counted within 800 m Euclidean buffers around public primary, middle and high schools in 97 US counties. Counties were randomly selected proportionate to county population size in 2011. Generalized linear mixed models were used to examine the association of school racial/ethnic composition and participation in free/reduced price lunch programs with fast food restaurant and tobacco outlet availability near schools.

Results: Nearly 40% of schools had both a fast food restaurant and a tobacco outlet within 800 m (approximately a 10 minute walk). The odds of having both a fast food restaurant and tobacco outlet within 800 m increased by 5% for every 10% increase in the percentage of Hispanic students (OR 1.05, 95% CI 1.03, 1.07). Odds increased by 3% for every 10% increase in the percentage of students receiving free/reduced price lunch (OR 1.03, 95% CI 1.01, 1.05). High schools had nearly 1.5 times the odds of having both a fast food restaurant and a tobacco outlet within 800 m compared with primary schools.

Conclusion: Low income and Hispanic students, and high school students are disproportionately exposed to both fast food restaurants and tobacco outlets near schools in this sample of 97 US counties. Restricting the location of fast food and tobacco retail outlets in school neighborhoods may help reduce access to harmful products, particularly among some vulnerable populations.

Citation Format: Heather D'Angelo, Alice Ammerman, Penny Gordon-Larsen, Laura Linnan, Leslie Lytle, Kurt M. Ribisl. Is the availability of fast food restaurants and tobacco outlets near schools in 97 U.S. counties associated with school sociodemographic characteristics? [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A70.
Abstract A71: Modification of obesity associations with prostate cancer grade by area-level factors
Authors: Scales Renyta , Spangler Elaine , Morales Knashawn , Glanz Karen , Rebbeck Timothy , Zeigler-Johnson Charnita
Published: May 2016

Purpose: Area-level characteristics have been associated with differences in rates of disease among populations. Specific factors, such as neighborhood socioeconomic status (SES), may influence overall exposure to risk factors and modify disease outcomes. The role of obesity in prostate cancer (PCa) progression has been confirmed with most studies showing a relationship to advanced disease and increased risk for biochemical failure and mortality. Although obesity and prostate cancer rates vary geographically, it is unclear if the relationship between obesity and PCa outcomes is modified by neighborhood factors. We evaluated the association of obesity with prostate cancer grade by area-level factors in a patient cohort recruited between 1995 and 2011.

Materials and Methods: A total of 949 patients were studied to evaluate whether the association of obesity with prostate tumor grade at diagnosis varied by residential neighborhood and county characteristics. Residential characteristics were obtained using PolicyMap data sources including the US Census, CDC data, and a regional survey collected biannually (CHDB). There were 680 non-obese and 269 obese patients. High tumor grade was defined as a Gleason Score ≥7. We analyzed the relationship between obesity and PCa grade using logistic regression models, adjusted for age and race. Similar models stratified by residential characteristics were assessed.

Results: Obese patients were more likely to have a high PCa grade compared to the non-obese patients (OR=1.47, 95% CI= 1.10-1.96). Associations between obesity and PCa grade were also observed for individuals residing in areas with higher rates of poverty (OR=1.57, 95% CI= 1.02-2.42), lower income (OR=1.56, 95% CI= 1.01-2.41), and lower education (OR=1.68, 95% CI= 1.12-2.52). The odds ratio was increased in areas with high rates of burglary (OR=1.55, 95% CI= 1.04-2.30) and murder (OR=1.51, 95% CI= 1.01-2.25) and low rates of robbery (OR=1.63, 95% CI= 1.03-2.58). In addition, obese men in areas with low rates of prostate cancer incidence (OR=1.84, 95% CI= 1.20-2.82) and low rates of obesity (OR=1.64, 95% CI= 1.02-2.63) also were likely to have a high grade PCa.

Conclusions: Associations between obesity and prostate cancer vary significantly by area-level SES, crime, and health indicators. These results suggest specific neighborhood characteristics that may help identify high risk groups and pathways for interventions.

Citation Format: Renyta Scales, Elaine Spangler, Knashawn Morales, Karen Glanz, Timothy Rebbeck, Charnita Zeigler-Johnson. Modification of obesity associations with prostate cancer grade by area-level factors. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A71.
Abstract A77: Walking and vigorous exercise and risk of breast cancer in African American women
Authors: Gong zhihong , Hong Chi-Chen , Bandera Elisa , Adams-Campbell Lucile , Park Song-Yi , Zirpoli Gary , Olshan Andrew , Ambrosone Christine , Palmer Julie , Rosenberg Lynn
Published: May 2016

The relationship between physical activity and breast cancer risk has been extensively studied among women of European descent, with most studies reporting an inverse association. However, data on African American (AA) women and by tumor subtypes are sparse. Thus, we examined associations of vigorous exercise and walking for exercise and breast cancer risk overall and by estrogen receptor (ER) status in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. We pooled data on AA women from four large studies, the Black Women's Health Study, Carolina Breast Cancer Study, Multiethnic Cohort Study and Women's Circle of Health Study, for 2,482 ER+ cases, 1,374 ER- cases and 16,959 controls. Multivariable logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) for the risk of overall breast cancer, and polytomous logistic regression was used to model the risk of ER+ and ER- cancer. Based on all four studies, for recent vigorous exercise (reported by 29% of controls), the OR was 0.88 (95% CI: 0.81-0.96) for breast cancer overall, 0.88 (95% CI: 0.80-0.98) for ER+ breast cancer and 0.93 (95% CI: 0.82-1.06) for ER- breast cancer. There was a statistically significant trend across hours per week of vigorous activity for breast cancer overall (p for trend=0.006) and for ER+ cancer (p for trend=0.02), but there was not a clear dose response relationship, with the strongest reduced risk in the 1-2 and 3-4 hours/week categories. Data on walking for exercise, as the most frequently reported activity among adults who meet guidelines for regular physical activity (53% in controls), was available from two studies. Any walking for exercise was associated with reduced risk of breast cancer overall (OR=0.88, 95% CI: 0.80-0.97) and ER+ cancer (OR=0.87, 95% CI: 0.77-0.98), but not ER- cancer (OR=0.95, 95 CI: 0.81-1.12). There was a significant trend across hours per week of walking for breast cancer overall (p for trend=0.008) and ER+ breast cancer (p for trend=0.02), with the strongest reduced risk in the 5+ hours/week category. Our results from this large pooling study of AA women provide evidence that vigorous exercise and walking for exercise are associated with reduced risk of breast cancer, specifically ER+ cancer.

Citation Format: zhihong Gong, Chi-Chen Hong, Elisa Bandera, Lucile Adams-Campbell, Song-Yi Park, Gary Zirpoli, Andrew Olshan, Christine Ambrosone, Julie Palmer, Lynn Rosenberg. Walking and vigorous exercise and risk of breast cancer in African American women. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A77.
Abstract A81: Relationship between out-of-pocket cost and use of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia
Authors: McDougall Jean A. , Bennette Caroline S. , Ramsey Scott D. , Sullivan Sean D.
Published: May 2016

Targeting tyrosine kinase activity in cancer cells represents one of the greatest innovations in cancer treatment. Yet the high cost of tyrosine kinase inhibitors (TKIs) and the cumulative financial burden to patients associated with their use may lead to disparities in medication adherence. This study investigated the relationship between out-of-pocket cost and adherence to TKIs among a cohort of commercially insured chronic myeloid leukemia (CML) patients. The Truven Health Marketscan database was used to identify prevalent cases of CML with >1 prescription claim for a guideline-recommended first-line TKI, imatinib, nilotinib, or dasatinib. Out-of-pocket cost was calculated longitudinally using any amount paid by the patient towards a deductible, copayment, and coinsurance. Adherence was assessed using the medication possession ratio (MPR), calculated between the first and last TKI claims occurring between 2011 and 2013, and conditional on continuous insurance plan enrolment. Nonadherence was classified as an MPR <80%. In addition to out-of-pocket cost, insurance plan, region, and area-level socioeconomic variables were assessed as determinants of adherence using logistic regression modeling to calculate and odds ratio (OR) and 95% confidence interval (CI). A total of 5,669 CML patients were identified from the Marketscan database between 2011 and 2013. Over that time period out-of-pocket costs for a 30-day supply of TKIs ranged from $0 to $1800, with means of $60 for dasatinib, $65 for imatinib, and $72 for nilotinib. Patients with relatively higher out-of-pocket costs (highest 75th percentile) were 27% more likely (OR 1.27, 95% 1.22 – 1.32) to be nonadherent to TKI therapy than patients with lower out-of-pocket costs. With the possibility of a generic version of imatinib on the horizon, understanding the association between out-of-pocket costs and adherence may have important implications for reducing disparities in adherence to TKIs for the treatment of CML.

Citation Format: Jean A. McDougall, Caroline S. Bennette, Scott D. Ramsey, Sean D. Sullivan. Relationship between out-of-pocket cost and use of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A81.
Abstract A89: Estimating potential years of life lost and productivity lost due to avoidable premature colorectal cancer deaths in U.S. counties with lower educational attainment
Authors: Weir Hannah K. , Li Chunyu , Henley Jane , Joseph Djenaba
Published: May 2016

Background: Measures of socioeconomic status (SES) are inversely associated with colorectal cancer (CRC) mortality. This study aims to estimate potential years of life lost and productivity lost due to premature cancer deaths among United States residents of lower SES areas, as measured by percentage of high school graduates. Methods: 2008-2012 mortality and population data were used to estimate the number of expected CRC deaths between the ages of 50-74 years by applying the mortality rate from higher SES areas (≥85% high school graduation) to lower SES areas, by race/ethnicity, age, and gender. Excess deaths (observed minus expected deaths) were used to estimate the years of potential life lost (YPLL) and the human capital method was used to estimate productivity lost due to YPLL. Results: Risk of CRC deaths was inversely associated with SES among non-Hispanic whites, non-Hispanic blacks and Hispanics. Of the 85,484 CRC deaths during 2008-2012 in lower SES groups, 16.8% (n=14,398) were potentially preventable if the CRC mortality rates in all areas were the same as higher SES areas. Eliminating avoidable CRC deaths would result in $4.2 billion in productivity gains in men and $2.2 billion in women based on a 3% discount rate. Conclusion: A substantial number of CRC deaths are potentially preventable through routine colorectal screening. SES disparities represent a large number of these deaths and result in a large economic burden in lower SES areas. Eliminating educational disparities could help decrease CRC cancer deaths and associated productivity lost in the US. These estimates do not include the costs to diagnose, treat and care for CRC patients.

Citation Format: Hannah K. Weir, Chunyu Li, Jane Henley, Djenaba Joseph. Estimating potential years of life lost and productivity lost due to avoidable premature colorectal cancer deaths in U.S. counties with lower educational attainment. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A89.
Abstract B51: An interferon λ 4 genotype is linked to a gene expression signature in prostate tumors of African American men
Authors: Jordan Symone , Tang Wei , Wallace Tiffany , Dorsey Tiffany , Yi Ming , Stephens Robert , Prokunina-Olsson Ludmila , Ambs Stefan
Published: May 2016

Not all segments of the U.S. population have equally benefited from the advances in our knowledge and treatment of cancer. As a result, African-American (AA) men still have the highest prostate cancer mortality among all U.S. racial and ethnic groups. In a recent study, we examined the tumor biology of prostate cancer comparing AA patients with European-American (EA) patients using large scale gene expression profiling and found significant differences in gene expression that are consistent with race/ethnic differences in the tumor microenvironment and immunobiology. Intriguingly, an interferon gene signature was detected in AA prostate that may relate to an unknown etiologic agent in disease pathology. This signature occurred commonly in AA men in two independent patient cohorts and may influence therapeutic outcome because it is analogous to a recently discovered interferon-related DNA damage resistance signature (termed IRDS), which predicts resistance to chemotherapy and radiation in breast cancer and perhaps other epithelial cancers. Here, we assessed whether the development of this signature could be functionally linked to a germline variant allele (rs368234815-ΔG) that is frequently found in subjects of African ancestry (~65% allele frequency) but is less common in subjects of European ancestry (~30% allele frequency). Carriers of ΔG can express a recently discovered interferon, termed interferon lambda 4 (IFNL4), while the rs368234815-TT allele eliminates expression. We genotyped DNA from tumors that have previously been characterized for presence of the interferon signature and found that the ability to generate IFNL4 (in carriers of the ΔG allele) was significantly associated with the presence of this signature (P < 0.001, n = 44), indicating that IFNL4 expression may be involved. In summary, our study links a germline genetic variant in IFNL4 to the occurrence of a clinically relevant interferon signature in prostate tumors of African-American men. Future research will assess how this genetic variant may influence disease outcome.

Citation Format: Symone Jordan, Wei Tang, Tiffany Wallace, Tiffany Dorsey, Ming Yi, Robert Stephens, Ludmila Prokunina-Olsson, Stefan Ambs. An interferon λ 4 genotype is linked to a gene expression signature in prostate tumors of African American men. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B51.
Abstract C51: Ethnic differences in the relationship between diabetes, early age adiposity, and mortality among breast cancer survivors: The Breast Cancer Health Disparities Study
Authors: Connor Avonne E. , Visvanathan Kala , Baumgartner Kathy B. , Baumgartner Richard N. , Boone Stephanie D. , Hines Lisa M. , Giuliano Anna R. , Wolff Roger K. , John Esther M. , Slattery Martha L.
Published: May 2016

Hispanic women have a high prevalence of type 2 diabetes and obesity. Breast cancer (BC) has become the leading cause of death among Hispanic women. Limited information exists on the relationship between diabetes, obesity, and mortality in Hispanic women diagnosed with BC. In a multicenter study we examined the associations between diabetes, obesity measures and survival outcomes. The study included 1,180 Hispanic and 1,298 non-Hispanic white (NHW) women who were diagnosed with incident invasive BC from the San Francisco Bay Area, New Mexico, Utah, Colorado and Arizona. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards regression models. The median follow-up time from BC diagnosis to death was 10.8 years and 267 of 466 deaths that occurred were from BC. Diabetes was significantly associated with BC-specific mortality (HR, 1.63 95% CI 1.08-2.47), with a stronger association among Hispanics (HR, 1.85 95% CI 1.11-3.09) compared to NHWs (HR, 1.33 95% CI 0.67-2.62). Among diabetic Hispanic women with estrogen receptor negative tumors, BC-specific mortality was increased three-fold (HR, 2.93 95% CI 1.09-7.88). In contrast, obesity at age 30 years was positively associated with BC-specific mortality in NHW women after adjusting for diabetes and known prognostic factors (HR, 2.33 95% CI 1.36-3.97, p interaction< 0.05), but not in Hispanics. In conclusion, we observed differences in the prognostic significance of diabetes and obesity by ethnicity among women with BC. Larger prospective studies are needed to evaluate ethnic differences in associations between diabetes and mortality for less common BC subtypes.

Citation Format: Avonne E. Connor, Kala Visvanathan, Kathy B. Baumgartner, Richard N. Baumgartner, Stephanie D. Boone, Lisa M. Hines, Anna R, Giuliano, Roger K. Wolff, Esther M. John, Martha L. Slattery. Ethnic differences in the relationship between diabetes, early age adiposity, and mortality among breast cancer survivors: The Breast Cancer Health Disparities Study. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C51.
Abstract C63: Elucidating the role of AIB1 in triple-negative breast cancer cell lines
Authors: Saenz Francisco R. , Riegel Anna T.
Published: May 2016

Triple negative breast cancer (TNBC) patients do not benefit from directed therapy because these tumors do not express targetable molecules; such as, hormone or growth factor receptors (ER, PR and HER2). This subtype represents 15-20% of all breast cancer cases diagnosed in women in the United States. Higher incidence of TNBC affects, particularly, young African American women compared with other women. Clinically, TNBC patients often present an advanced stage disease. These tumors exhibit an increased inflammatory signal and an aggressive phenotype that leads to an increased frequency of metastasis. These patients have a poor survival outcome. Coincidentally, expression of the amplified in breast cancer 1 (AIB1) oncogene has also been reported in higher grade, inflammatory and invasive breast cancer. AIB1 is a nuclear coactivator that regulates transcription of several genes through hormone and/or growth factor signaling. Here we demonstrate that cell lines derived from tumors in African American women representing different TNBC subtypes have varying degree of sensitive to AIB1 shRNA by lentiviral infection. AIB1 knockdown has a considerable effect on viability of all the TNBC subtypes; however, we observed the presence of a small fraction of cells that proliferate independent of AIB1. Interestingly, these cells that retain the AIB1 knockdown following sub-culture for 3-4 passages are comparable to the initial TNBC cells as regards to cell cycle and apoptosis. Intriguingly, these TNBC cells that proliferate independent of AIB1 show increase in the percentage of cells expressing CD44+/CD24- cell surface markers indicating a selection of tumor initiating cells. Concomitantly, there is a decrease in the percentage of CD44-/CD24- cells suggesting that AIB1 may regulate tumor initiating cell differentiation upon external stresses such as those caused by chemotherapeutic agents during treatment. We will further study the chemo sensitivity of TNBC cells resistant to AIB1 loss and assess whether these cells represent a model of cancer cell dormancy associated to recurrence in TNBC patients.

Citation Format: Francisco R. Saenz, Anna T. Riegel. Elucidating the role of AIB1 in triple-negative breast cancer cell lines. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C63.