Anne Ford

Factors affecting compliance with clinical practice guidelines for pap smear screening among healthcare providers in africa: systematic review and meta-summary of 2045 individuals.

Background Although the importance of the Pap smear in reducing cancer incidence and mortality is known, many countries in Africa have not initiated yet widespread national cervical cancer screening programs. The World Health Organization (WHO) has published Clinical Practice Guidelines (CPGs) on cervical cancer screening in developing countries; however, there is a gap between expectations and clinical performance. Thus, the aim of this study was to conduct a systematic review and meta-summary to identify factors affecting compliance with CPGs for Pap screening among healthcare providers in Africa. Methods And Findings: MEDLINE, Scirus, Opengate and EMBASE databases were searched in January 2012. Studies involving medical personnel practicing in Africa, whose outcome measured any factors that affect medical personnel from using a Pap smear to screen for cervical cancer, were included. Two reviewers independently evaluated titles and abstracts, then full-texts, extracted data and assessed quality of the included studies. A descriptive analysis of the included studies was conducted. We calculated Frequency effect sizes (FES) for each finding and Intensity effect sizes (IES) for each article to represent their magnitudes in the analyses. Of 1011 studies retrieved, 11 studies were included (2045 individuals). Six different themes related to the factors affecting compliance with CPGs were identified: Insufficient Knowledge/Lack of awareness (FES = 82%), Negligence/Misbeliefs (FES = 82%), Psychological Reasons (FES = 73%), Time/Cost Constraint (FES = 36%), Insufficient infrastructure/training (FES = 45%) and also no reason given (FES = 36%). IES for articles ranged between 33 and 83%. Conclusions These results suggest that prevention initiatives should be comprehensive to include education and resources needs assessments and improvement, Pap smear test training, strategies on costing, and practitioner time studies.

Protein Microarray Analysis of Mammary Epithelial Cells from Obese and Nonobese Women at High Risk for Breast Cancer: Feasibility Data

Background: Obesity is a well-established risk factor for cancer, accounting for up to 20% of cancer deaths in women. Studies of women with breast cancer have shown obesity to be associated with an increased risk of dying from breast cancer and increased risk of developing distant metastasis. While previous studies have focused on differences in circulating hormone levels as a cause for increased breast cancer incidence in postmenopausal women, few studies have focused on potential differences in the protein expression patterns of mammary epithelial cells obtained from obese versus nonobese women. Methods: Protein expression was assessed by reverse-phase protein microarray in mammary epithelial cells from 31 random periareolar fine needle aspirations performed on 26 high-risk women. Results: In this pilot and exploratory study, vimentin (unadjusted P = 0.028) expression was significantly different between obese and nonobese women. Conclusions: Vimentin is integral both to adipocyte structure and function and to the epithelial-to-mesenchymal transition needed for cancer cell metastasis. Further research is needed to confirm this finding and determine the possible effects of the adipocyte microenvironment on the initiation and progression of breast cancer in high-risk women. Impact: Differential protein expression patterns obtained from a future expanded study may serve to elaborate the underlying pathology of breast cancer initiation and progression in obese women and identify potential biomarkers of response to preventative interventions such as dietary changes and exercise. Cancer Epidemiol Biomarkers Prev; 20(3); 476–82. ©2011 AACR.

Abstract B01: PEG3 DNA methylation and cervical intraepithelial neoplasia in African American and European American women

Background: Epigenetic mechanisms are hypothesized to be etiologically involved in progression of cervical intraepithelial neoplasia (CIN) to invasive cervical cancer (ICC), although empirical data are lacking. Methods: A total of 304 women were enrolled at the time of colposcopic evaluation following an abnormal liquid-based cytology screen. HPV was genotyped by HPV linear array. To ascertain the presence of CIN, the biopsies underwent pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of IGF2/H19 PEG1/MEST, KCNQ1OT1, MEG3, HYMAI, PEG10 and PEG3 imprinted domains, using Sequenom EpiTYPER assays. Logistic regression models were used to estimate odd ratios (ORs) and to evaluate the associations between HPV infection and DMR methylation, respectively. Results: After accounting for age, HPV infection, parity, hormonal contraceptive use, and cigarette smoking, methylation differences at the PEG3 DMR were associated with a modest but significant higher risk of CIN2/3 (OR=1.08, 95%CI 1.02-1.18, p=0.022) in all women. This association remained significant in European American (OR=1.13, 95%CI 1.03-1.27, p=0.011), but not in African American women (OR=1.03, 95%CI 0.90-1.16, p=0.715). HPV infection was associated with altered PEG3 DMR methylation in both groups of women, an association that was also stronger in European Americans (β= -3.42, p=0.041), than in African Americans (β= -2.55, p=0.132). Though altered methylation at IGF2/H19 and PEG10 DMRs was associated with CIN1, no associations were observed with CIN2/3 lesions. No associations were found for PEG1/MEST, KCNQ1OT1, MEG3, and HYMAI DMRs. Conclusions: Aberrant DNA methylation at the regulatory region of the PEG3 imprinted gene may increase susceptibility to CIN2/3; an association that may be stronger in European American women and which persisted after accounting for HPV infection. If confirmed in larger studies, these findings support the hypothesis that DNA methylation at PEG3 may represent a susceptibility locus that can be exploited to identify, from among a large number of abnormal colposcopy cases, those likely to progress to CIN or worse. Citation Format: Adriana C. Vidal, David Skaar, Zhiquing Huang, Fidel Valea, Rex Bentley, Margaret Gradison, Kimberly S. H. Yarnall, Anne Ford, Francine Overcash, Katherine Grant, Susan K. Murphy, Cathrine Hoyo. PEG3 DNA methylation and cervical intraepithelial neoplasia in African American and European American women. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B01.

HPV Genotypes and Cervical Intraepithelial Neoplasiain a Multiethnic Cohort in the Southeastern United States

Background: For poorly understood reasons, invasive cervical cancer (ICC) incidence and mortality rates are higher in women of African descent. Oncogenic human papillomavirus (HPV) genotypes distribution may vary between European American (EA) and African American (AA) women, and may contribute to differences in ICC incidence. Methods: Five-hundred and seventy-two women were enrolled at the time of colposcopic evaluation following an abnormal liquid-based cytology screen. HPV infections were detected using HPV-linear array, and chi-squared tests and linear regression models were used to compare HPV genotypes across racial/ethnic groups by CIN status. Results: Of the 572 participants, 494 (86%) had detectable HPV; 245 (43%) had no CINlesion, 239 (42%) had CIN1, and 88 (15%) had CIN2/3. Seventy-three percent of all women were infected with multiple HPV genotypes. After adjusting for race, age, parity, oral contraception use and current smoking, AAs were two times less likely to harbor HVP16/18 (OR=0.52, 95%CI 0.27-0.98, p=0.04) when all women were considered. This association remained unchanged when only women with CIN2/3 lesions were examined (OR=0.22, 95%CI 0.05-0.95, p=0.04). The most frequent high risk (HR)-HPV genotypes detected among EAs were 16, 18, 56, 39 and 66, while HPV genotypes 33, 35, 45, 58 and 68 were the most frequent ones detected in AAs.

Abstract PR01: HPV genotype distribution and cervical intraepithelial neoplasia in African American and white women living in the Southeastern United States

Background: Differential distributions of oncogenic HPV genotypes among racial/ethnic groups may explain observed disparities in ICC incidence and mortality rates. We describe HPV genotypes associated with CIN1-3 in a multiethnic cohort of women visiting colposcopy clinic following a cervical abnormality. Methods: We enrolled 516 women attending colposcopic evaluation following an abnormal liquid-based cytology screen. HPV infection was measured using HPV linear array that measures 37 HPV types, and chi-squared tests were used to compare HPV genotypes in African American and Whites overall, and by CIN stage. Results: Of 516 participants, 373 (72%) were HPV-positive; 137 (37%) had no CIN lesion, 174 (47%) had CIN1, 38 (10%) had CIN2, and 24 (6%) had CIN-3. Twenty-seven percent of women were infected with one HPV genotype, and 73% were infected with multiple HPV genotypes. In women with CIN1, 75% of HPV single infections were of high risk (HR) genotypes, and 70% of women had multiple HR-HPV genotype infections. The most frequent HR-HPV genotypes detected among CIN1 cases were 16, 18, 31, 45, 52, 56, 59 and 66 in White women, while HPV subtypes 33, 35, 58 and 68 were the most common in African American women. Restricting analyses to women with CIN2-3 revealed a change in HR-HPV genotype distribution; HR-HPV 16, 18, 33, 35, 39, and 59 were most common in White women with CIN2-3, whereas HR-HPV 31, 45, 51 and 66 were the most prevalent in African American women. Conclusion: Our data suggest that while HPV 16 and 18 are the most common genotypes among women with CIN in Whites; African Americans may harbor different genotypes. The preponderance of non-16/18 HR-HPV genotypes in African Americans with increasing CIN grade has implications for both reflex testing following cytological abnormalities and vaccine development. This abstract is also presented as Poster B11. Citation Format: Adriana C Vidal, Jennifer S Smith, Edwin Iversen, Fidel Valea, Rex Bentley, Margaret Gradison, Kimberly Yarnall, Anne Ford, Francine Overcash, Katherine Grant, Susan Murphy, Cathrine Hoyo. HPV genotype distribution and cervical intraepithelial neoplasia in African American and white women living in the Southeastern United States. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PR01.

Erratum: Pilot and feasibility study: Prospective proteomic profiling of mammary epithelial cells from high-risk women provides evidence of activation of pro-survival pathways (Breast Cancer Research and Treatment (2012) 132 (487-498) DOI: 10.1007/s10549-011-1609-9)

Catherine Ibarra-Drendall • Michelle M. Troch • William T. Barry • Gloria Broadwater • Emanuel F. Petricoin III • Julia Wulfkuhle • Lance A. Liotta • Siya Lem • Joseph C. Baker Jr. • Anne C. Ford • Lee G. Wilke • Carola Zalles • Nicole M. Kuderer • Abigail W. Hoffman • Melanie Shivraj • Priya Mehta • Jamila Williams • Nora Tolbert • Laurie W. Lee • Patrick G. Pilie • Dihua Yu • Victoria L. Seewaldt

Abstract CN07-03: IL6 and AKT as targets for chemoprevention

Background: Currently we lack adequate prevention strategies for triple-negative breast cancer; progress in designing targeted strategies is limited by a lack of knowledge of the biology of cancer initiation. The origins of triple-negative breast cancer in premenopausal women are poorly understood. Importantly, we do not understand whether the molecular pathways that underlie the aggressive behavior of triple-negative breast cancer can be detected in premalignant breast lesions. Growing evidence indicates that early mammary carcinogenesis is regulated by integrated signaling networks and not by isolated genes. Interleukin-6 (IL6) plays a role in stem cell regeneration, promotes epithelial to mesenchymal transition (EMT), and high IL6 serum levels predict a poor outcome in premenopausal women with triple-negative breast cancer. Methods and Results: We used Reverse-Phase Protein Microarray (RPPM) profiling to test for activation of phosphoprotein signaling in premalignant Random Periareolar Fine Needle Aspiration (RPFNA) mammary epithelial cytology from 65 high-risk African American women. Unsupervised hierarchical clustering of RPPM proteomic analysis RPFNA aspirates identified three activated ER− signaling pathways including co-activation of Akt/mTOR/PI3K and IL6/pStat3/vimentin. Analysis of interstitial breast tissue demonstrated that high interstitial IL6/VEGF cytokine production predicted high epithelial expression of pStat3/vimentin. Based on these observations we are currently launching a prevention trial to target Akt/mTor using metformin 500 mg bid. Conclusion: This is the first demonstration that Akt/mTor and IL6/Stat3/vimentin signaling is activated in pre-cancerous mammary epithelial cells from high-risk premenopausal women. Currently we are testing whether trials are on-going to test whether metformin can inhibit activation of mammary epithelial Akt/mTor and perhaps IL6/Stat3/vimentin signaling. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN07-03.

Abstract B9: Community strategies for investigating the biology of breast and cervical cancer initiation in African-American women

Background: African-American women have the highest overall cancer death rate from breast and cervical cancer and shortest survival of any racial and ethnic group in the United States. These disparities are heightened in the Southern United States. For example, the US breast cancer death rate is 23.0 (per 100,000) for Caucasian women, as compared to 34.3 for African-American women. The North Carolina breast cancer death rate is 27.2 for Caucasian women and 38.0 for African Americans; and in our study area, Durham County, the breast cancer death rate is 27.5 for Caucasians and 42.0 for African-Americans. The causes of these inequalities are complex and interrelated, but arise, at least in part, from disparities in income, education, nutrition, and access to healthcare. For complex historical reasons, African-Americans have had mixed experiences in accessing care and in the quality of care they receive. In addition, distrust has arisen within the African-American community regarding the intents and purposes of health care researchers. Cutting edge breast imaging technology, prevention, and early detection trials exist at academic that could potentially improve early diagnosis and increase our chance of understanding the complex relationship between disparities, genetics, diet, and the environment in promoting breast cancer. Lack of access, mistrust, and community barriers all play a key role in preventing young African-American women from benefiting from state-of-the-art breast imaging and new strategies for early detection of breast and cervical cancer. Methods and Results: To address the unacceptably high death rate among young African-American women from breast and cervical cancer, we have used a multi-disciplinary intervention that includes: 1) community Navigators, 2) access to breast and cervical cancer prevention and early detection services through free community clinics, 3) community partnered breast and cervical cancer prevention trials, and 4) opportunities for mentorship and career development. As a result, we have been able to improve access to early detection strategies in a community based setting and have provided mentorship for 27 young Minority scholars to enter medical school and graduate programs. Our community based breast MRI trial for underserved women has performed over 600 breast MRI since 2004. Over 50% of these women entered in this trial are Women-of-Color. Conclusion: A community based strategy can be highly successful for improving early detection of breast and cervical cancer but only if there is community participation during the initiation of clinical trials and joint community-academic mentorship of young Minority Scholars. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B9.

Abstract A20: Random periareolar fine‐needle aspiration is highly reproducible in a CALGB multi‐institutional cross‐sectional study

Background: Biomarkers that vary with risk and response to prevention interventions are referred to as “surrogate endpoint biomarkers”. As outlined by Fabian et al., surrogate endpoint biomarkers should be 1) biologically and statistically significantly associated with cancer development, 2) present in a reasonable proportion of at‐risk individuals, 3) obtainable by minimally invasive procedures, and 4) reversible with prevention interventions that have been validated to decrease cancer incidence. Many modalities have been suggested as potential surrogate endpoint biomarkers for breast cancer, including mammographic density, serum biomarkers, and breast tissue biomarkers. Currently, there is no consensus as to the optimal surrogate endpoint biomarker. Random Periareolar Fine Needle Aspiration (RPFNA) is a research technique developed to assess short‐term breast cancer risk in women at increased risk for breast cancer. While there is increasing acceptance of RPFNA, neither the reproducibility nor the inter‐institutional compatibility of RPFNA has been established. To address these key limitations, the Cancer and Leukemia Group B (CALGB) Prevention Group tested the reproducibility of RPFNA in a multi‐institutional cross‐sectional study. Methods: Sixty‐three high‐risk women from five CALGB institutions (Duke, Ohio State, Roswell Park, Dana‐Farber, and Vermont) underwent RPFNA from July 1, 2007 to June 30, 2008. Duplicate bilateral RPFNA was performed on each woman by a single investigator on a single day. Masood Cytology Index score was assessed by a single blinded cytopathologist. Results: There was a high degree of statistical agreement in the Masood Cytology Index scores of duplicate RPFNA samples from the same breast, with a Spearman correlation coefficient of 0.8312 (p Conclusions: This multi‐institutional study demonstrates that RPFNA is a highly reproducible measure of breast cytology in a cooperative group cross‐sectional trial. RPFNA did not demonstrate a high degree of agreement between breasts, suggesting that breast cancer risk and progression may occur at different rates in individual breasts from a single woman. These data provide important validation of the reproducibility of RPFNA in a multi‐institutional cross‐sectional study that included cohorts that varied in demographic composition. Important future directions will include a larger RPFNA cohort study and testing for the reproducibility of RPFNA samples with atypia before and after administration of chemoprevention agents. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A20.