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Background: We evaluate the cost-effectiveness of HPV self-collection (followed by scheduling assistance for those who were HPV+ or inconclusive) compared to scheduling assistance only and usual care among underscreened persons with a cervix (PWAC). Methods: A decision tree analysis was used to estimate the incremental cost-effectiveness ratios (ICERs), or the cost per additional PWAC screened, from the Medicaid/state and clinic perspectives. A hypothetical cohort represented 90,807 low-income, underscreened individuals. Costs and health outcomes were derived from the MyBodyMyTest-3 randomized trial except the usual care health outcomes were derived from literature. We performed probabilistic sensitivity analyses (PSA) to evaluate model uncertainty. Results: Screening uptake was highest in the self-collection alternative (n=65,721), followed by the scheduling assistance alternative (n=34,003) and usual care (n=18,161). The self-collection alternative cost less and was more effective than the scheduling assistance alternative from the Medicaid/state perspective. Comparing the self-collection alternative to usual care, the ICERs were $284 per additional PWAC screened from the Medicaid/state perspective and $298 per additional PWAC screened from the clinic perspective. PSAs demonstrated that the self-collection alternative was cost-effective compared to usual care at a willingness-to-pay threshold of $300 per additional PWAC screened in 66% of simulations from the Medicaid/state perspective and 58% of simulations from the clinic perspective. Conclusion: Compared to usual care and scheduling assistance, mailing HPV self-collection kits to underscreened individuals appears to be cost-effective in increasing screening uptake. Impact: This is the first analysis to demonstrate the cost-effectiveness of mailed self-collection in the US.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Supplemental Figures 1-2

Supplementary Data Legends

PDF file, 69K, Appendix Table A: Codes Used to Identify Procedures.

PDF file, 60K, Appendix Figure A: Change in Median Procedure Cost between 2001 and 2006.

PDF file, 59K, Appendix Table B: Procedures by Age Group.

PDF file, 59K, Appendix Table E: Median (Mean SD) Cost Per Procedure in 2005 for HPV Vaccination Target Age Groups.

PDF file, 58K, Appendix Table D: Median (Mean SD) Cost Per Procedure, 2001-2006, by Age Group.

Background: Oncogenic types of human papillomavirus (HPV) have been linked to 99.7% of cervical cancer cases worldwide.Methods: This retrospective claims-based analysis was conducted to assess patterns of use and costs associated with diagnostic and treatment procedures for disease attributed to HPV performed before the introduction of HPV vaccination (January 1, 2001–May 31, 2006). Percentages of commercially insured health plan enrollees who underwent each procedure of interest were calculated for each year. Annual costs (combined patient and health plan-paid amounts) were calculated from qualifying medical claims. Descriptive statistics were used to assess trends in procedure rates and costs.Results: Data for approximately 14.2 million enrollees were obtained. Hysterectomy was the most commonly administered treatment. With the exception of colposcopy with LEEP, all other treatment procedures experienced a decline in rate of use. The most frequently performed diagnostic procedure was colposcopy with endocervical curettage (ECC). With the exception of ECC, rates of diagnostic procedures reached a peak among 20- to 24-year-olds, and followed a downward trend across older groups. Hysterectomy was the most expensive treatment (median $7,383; mean $8,384) per procedure in 2006.Conclusion: Results reveal high rates of use and high-associated costs of diagnostic procedures and treatments related to disease attributed to HPV.Impact: The data presented may be useful in cost-effectiveness analyses and to guide decision makers evaluating how best to optimize prevention strategies. Cancer Epidemiol Biomarkers Prev; 21(9); 1469–78. ©2012 AACR.

Background: Male circumcision reduces the risk of human immunodeficiency virus infection in men. We assessed the effect of male circumcision on the incidence and natural history of human papillomavirus (HPV) in a randomized clinical trial in Kisumu, Kenya. Methods: Sexually active, 18- to 24-year-old men provided penile exfoliated cells for HPV DNA testing every 6 months for 2 years. HPV DNA was detected via GP5+/6+ PCR in glans/coronal sulcus and in shaft samples. HPV incidence and persistence were assessed by intent-to-treat analyses. Results: A total of 2,193 men participated (1,096 randomized to circumcision; 1,097 controls). HPV prevalence was 50% at baseline for both groups and dropped to 23.7% at 24 months in the circumcision group, and 41.0% in control group. Incident infection of any HPV type over 24 months was lower among men in the circumcision group than in the control group [HR = 0.61; 95% confidence interval (CI), 0.52–0.72]. Clearance rate of any HPV infection over 24 months was higher in the circumcision group than in the control group (HR = 1.87; 95% CI, 1.49–2.34). Lower HPV point-prevalence, lower HPV incidence, and higher HPV clearance in the circumcision group were observed in glans but not in shaft samples. Conclusion: Male circumcision reduced the risk of HPV acquisition and reinfection, and increased HPV clearance in the glans. Impact: Providing voluntary, safe, and affordable male circumcision should help reduce HPV infections in men, and consequently, HPV-associated disease in their partners.

Background: Primary high-risk human papillomavirus (hr-HPV) testing of self-collected cervico-vaginal swabs could increase cervical cancer screening coverage, although triage strategies are needed to reduce unnecessary colposcopies. We evaluated the use of extended hr-HPV genotyping of self-collected samples for cervical cancer screening. Methods: We recruited women ages 25–65 years at two colposcopy clinics in North Carolina between November 2016 and January 2019, and obtained self-collected cervico-vaginal samples, provider-collected cervical samples, and cervical biopsies from all enrolled women. Self- and provider-collected samples were tested for 14 hr-HPV genotypes using the Onclarity Assay (Becton Dickinson). We calculated hr-HPV genotype–specific prevalence and assessed agreement between results in self- and provider-collected samples. We ranked the hr-HPV genotypes according to their positive predictive value (PPV) for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN2+). Results: A total of 314 women participated (median age, 36 years); 85 women (27%) had CIN2+. More women tested positive for any hr-HPV on self-collected (76%) than on provider-collected samples (70%; P = 0.009) with type-specific agreement ranging from substantial to almost perfect. HPV-16 was the most common genotype in self-collected (27%) and provider-collected samples (20%), and HPV-16 prevalence was higher in self- than provider-collected samples (P < 0.001). In self- and provider-collected samples, HPV-16 had the highest PPV for CIN2+ detection. Conclusions: Overall sensitivity for CIN2+ detection was similar for both sample types, but the higher HPV-16 prevalence in self-collected samples could result in increased colposcopy referral rates. Impact: Additional molecular markers might be helpful to improve the triage of women who are hr-HPV positive on self-collected samples.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Background: High-risk human papillomavirus (hrHPV) testing is recommended for primary cervical cancer screening and is used alongside cytology to triage screening abnormalities to colposcopy. Most screening-based hrHPV tests involve pooled detection of any hrHPV type or of HPV 16/18 only. Extended HPV genotyping, particularly of non-16/18 hrHPV types, may improve risk stratification for millions of cervical abnormalities detected each year, but HPV genotype-specific progression risks are not well characterized. HPV genotype-specific incidence of high-grade cervical intraepithelial neoplasia or more severe (CIN2+) was examined among individuals with normal or low-grade (CIN1) histology following an abnormal screening cytology result. Methods: A US-based prospective, multiracial cohort of 343 colposcopy referral patients with normal (n=226) or CIN1 (n=117) histology was assessed. Baseline cervical samples underwent HPV DNA genotyping. Participants were followed for up to five years. Genotype-specific CIN2+ incidence rates (IR) were estimated with accelerated failure time models for interval-censored data. Cumulative CIN2+ risk over five years was estimated non-parametrically and compared for HPV risk groups (HPV 16/31/18, else HPV 33/58/52/45, else HPV 39/68/35/51/59/56/66) and age groups (ages 21-24, 25-29, 30+). Results: At enrollment, median participant age was 30.1 years; 67.1% were hrHPV-positive. During follow-up (median 24.3 months), 24 participants progressed to CIN2+ (7.0%; 6.2% among normal histology and 8.6% among CIN1). CIN2+ IR among hrHPV-positive participants was 3.2/1,000 person-months. CIN2+ IRs were highest for HPV 16 (IR 8.3; 95% CI 4.1, 16.6), HPV 33 (IR 7.8; 95% CI 2.0, 31.3), and HPV 58 (IR 4.9; 95% CI 1.2, 19.6). IRs were highest for HPV 16, 68, and 33 among normal histology and for HPV 33, 31, 16, and 58 among CIN1. Five-year CIN2+ risks were 0.27 for HPV 16/31/18, 0.11 for HPV 33/58/52/45, and 0.13 for HPV 39/68/35/51/59/56/66 (p=0.04). CIN2+ risk did not differ by age group. Conclusion: In addition to the established HPV type 16, HPV 33 and 58 were consistently predictive of progression to CIN2+ over a five-year period in this cohort. These findings also support the utility of HPV risk groups to stratify women with non-16/18 hrHPV positivity who exhibit differential risks of progression. Additionally, HPV risk groups appear to predict progression regardless of age; thus, although hrHPV testing is not recommended for initial screening of women under 30 years of age, it may be a risk-stratification tool for these younger women, once a cervical abnormality is found. In conclusion, extended genotyping of non-16/18 hrHPV may be useful to identify individuals with normal or low-grade histology results who are at increased risk of progression to CIN2+, thereby improving the efficacy of cervical cancer screening. Citation Format: Alexandra Bukowski, Cathrine Hoyo, Michael G. Hudgens, Wendy R. Brewster, Fidel Valea, Rex C. Bentley, Adriana C. Vidal, Rachel L. Maguire, John W. Schmitt, Susan K. Murphy, Kari E. North, Jennifer S. Smith. Extended human papillomavirus genotyping to predict progression to high-grade cervical precancer: A prospective cohort study in the southeastern United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2230.

Reducing cervical cancer disparities in the United States requires intentional focus on structural barriers such as systems and policy that impact access to human papillomavirus (HPV) vaccination, cervical cancer screening, and treatment. Such changes are difficult and often politicized. State comprehensive cancer control (CCC) plans are vehicles that, if designed well, can help build collective focus on structural changes. Study objectives were to identify the prioritization of cervical cancer in state CCC plans, the conceptualization of HPV within these plans, and the focus of plans on structural changes to reduce cervical cancer disparities. Data were gathered by systematic content analysis of CCC plans from 50 states and the District of Columbia from February–June 2014 for evidence of cervical cancer prioritization, conceptualization of HPV, and focus on structural barriers to cervical cancer vaccination, screening or treatment. Findings indicate that prioritization of cervical cancer within state CCC plans may not be a strong indicator of state efforts to reduce screening and treatment disparities. While a majority of plans reflected scientific evidence that HPV causes cervical and other cancers, they did not focus on structural elements impacting access to evidence-based interventions. Opportunities exist to improve state CCC plans by increasing their focus on structural interventions that impact cervical cancer prevention, detection, and treatment, particularly for the 41% of plans ending in 2015 and the 31% ending between 2016 and 2020. Future studies should focus on the use of policy tools in state CCC plans and their application to cervical cancer prevention and treatment. Cancer Prev Res; 8(7); 636–41. ©2015 AACR.

Background: Oncogenic types of human papillomavirus (HPV) have been linked to 99.7% of cervical cancer cases worldwide. Methods: This retrospective claims-based analysis was conducted to assess patterns of use and costs associated with diagnostic and treatment procedures for disease attributed to HPV performed before the introduction of HPV vaccination (January 1, 2001–May 31, 2006). Percentages of commercially insured health plan enrollees who underwent each procedure of interest were calculated for each year. Annual costs (combined patient and health plan-paid amounts) were calculated from qualifying medical claims. Descriptive statistics were used to assess trends in procedure rates and costs. Results: Data for approximately 14.2 million enrollees were obtained. Hysterectomy was the most commonly administered treatment. With the exception of colposcopy with LEEP, all other treatment procedures experienced a decline in rate of use. The most frequently performed diagnostic procedure was colposcopy with endocervical curettage (ECC). With the exception of ECC, rates of diagnostic procedures reached a peak among 20- to 24-year-olds, and followed a downward trend across older groups. Hysterectomy was the most expensive treatment (median $7,383; mean $8,384) per procedure in 2006. Conclusion: Results reveal high rates of use and high-associated costs of diagnostic procedures and treatments related to disease attributed to HPV. Impact: The data presented may be useful in cost-effectiveness analyses and to guide decision makers evaluating how best to optimize prevention strategies. Cancer Epidemiol Biomarkers Prev; 21(9); 1469–78. ©2012 AACR.

Background: An estimated one in eight cervical cancer cases is due to lack of follow-up care for abnormal Pap smear results. Low rates of completion of follow-up care particularly affect low-income and minority women and women from rural areas (SEER, 2014). The burden of cervical cancer could be significantly reduced through interventions that improve timely follow-up and treatment. Mobile communications via text messaging may present a low-cost opportunity to increase rates of clinic return among women referred to follow-up on abnormal primary cervical cancer screening results. Purpose: To determine the acceptability and feasibility of using text messaging as a means of increasing completion of follow-up care following an abnormal cervical cancer screening result. We also examined factors that may affect the acceptability and use of text messaging to increase communications between health care providers and low-income and minority women. Methods: Study participants were 15 African American and low-income women who had undergone a Pap smear within the preceding 12 months. Semistructured interviews, including open- and closed-ended questions from a validated questionnaire, were conducted by phone or in person, depending on participant preference. Data were analyzed using a mixed-methods approach. Responses to closed-ended survey items were tabulated and descriptive statistics generated using Excel. Responses to the open-ended questions were coded and analyzed using NVivo 11 qualitative analysis software. Results: Nearly all women in the study (93%) were comfortable receiving a text message from a health care provider stating that their Pap smear results were available (age Conclusions: Most participants indicated a willingness to receive text messages from their health care providers on the results of their cervical cancer screening and believed that text messages were the best way to remind them of their appointment for follow-up care. Concerns about privacy of health information could be addressed by minimizing reference to the nature of an appointment in the message. While text messaging seems promising to improve adherence to timely follow-up, personal preferences should be considered in the use of this technology--possibly by allowing patients to opt out of text communications. Further research is needed to assess the feasibility and effectiveness of this approach to improve adherence to follow-up in high-risk populations. Citation Format: LaHoma Smith Romocki, Leslie Cofie, Andrea Des Marais, Theresa Curington, Chelsea Anderson, Jennifer S. Smith. Acceptability of text messaging for communication of health information among Black and low-income women following abnormal cervical cancer screening [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B08.

Background: Differential access to basic health information may contribute to persistent cervical cancer disparities. We examined whether human papillomavirus (HPV) vaccine awareness, HPV knowledge, and use of information sources about the vaccine differ by sociodemographic characteristics associated with cervical cancer. Methods: Study participants (n = 889) were caregivers of adolescent girls ages 10 to 18 years living in southeastern North Carolina. Analyses simultaneously controlled for caregivers' gender, race, age, education, income, and rural residence. Results: Although most caregivers were aware of HPV (83%) and the HPV vaccine (82%), awareness differed by gender, race, education, and income. The largest differences were for race, with 87% of Whites versus 68% of African Americans having heard of the vaccine (P < 0.001). Caregivers correctly answered an average of 69% of questions on HPV, with differences by race and education. Most respondents heard of the HPV vaccine through drug company advertisements (83%) or broadcast media coverage (69%). African Americans were less likely than Whites to have heard about the vaccine from advertisements but more likely from a broadcast source (P < 0.05). Health care providers (88%) and the internet (65%) were the most favored sources for future information about the vaccine. Vaccine uptake was associated with awareness, knowledge, and media use. Discussion: Whereas drug company advertisements seem to play a central role in high HPV vaccine awareness, doctors and the internet are the preferred future “go to” sources for seeking out information. Communication-based interventions for caregivers from cervical cancer risk groups, especially African Americans, may need to use different communication channels and content. (Cancer Epidemiol Biomarkers Prev 2009;18(2):363–72)

Objective: This study aimed to estimate if risk factor profiles for histologically confirmed cervical intraepithelial neoplasia (CIN) 2 lesions differ from those for CIN 1 or 3. Methods: A total of 2,055 women positive for high-risk human papillomavirus, with a minimum of five cervical biopsies, were enrolled in the Shanxi Province Cervical Cancer Screening Study II. We evaluated risk factor profiles for CIN 2 in comparison with CIN 1 and 3. Polytomous logistic regression was used to generate odds ratios and corresponding 95% confidence intervals and to test for differences in odds ratios across histologic grades. Results: The risk for CIN 3 associated with three or more pregnancies and sexual intercourse within 4 months of childbirth was higher than that for CIN 2 (Pdifference = 0.02 and 0.0007, respectively). Significant differences in the associations of age groups with CIN 1 and 2 were observed, such that there were positive associations with CIN 2 but none for CIN 1. There was no difference in the association of number of sexual partners or reported number of abortions between CIN 1 and 2 or between CIN 3 and 2. Conclusions: In our study, the patterns of risk factor profiles for CIN 1, 2, and 3 were unique. Conventional grouping of CIN 2 with 3 for analysis of risk factors may need revisiting. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2350–5)

Low-grade squamous intraepithelial lesions (LSIL) associated with certain human papillomavirus (HPV) genotypes may preferentially progress to cervical cancer. HPV genotyping may thus have the potential to improve the effectiveness of screening programs and to reduce overtreatment. LSIL cases (n = 8,308) from 55 published studies were included in a meta-analysis. HPV genotype distribution was assessed by geographic region and in comparison with published data on cervical squamous cell carcinoma (SCC). HPV detection in LSIL was 80% in North America but less than 70% in other regions, most likely reflecting regional differences in LSIL diagnosis. Among 5,910 HPV-positive LSILs, HPV16 was the most common genotype (26.3%) followed by HPV31 (11.5%), HPV51 (10.6%), and HPV53 (10.2%). HPV-positive LSILs from Africa were 2-fold less likely to be infected with HPV16 than those in Europe, and HPV-positive LSILs from North America were more likely to be infected with HPV18 than those from Europe or South/Central America. Interpretation for rarer genotypes was hampered by variation in HPV testing methodology. SCC/LSIL prevalence ratios indicated that HPV16 was 2-fold and HPV18 was 1.5-fold more common in SCC than in HPV-positive LSIL, thus appearing more likely to progress than other high-risk genotypes (SCC/LSIL prevalence ratios between 0.05 and 0.85). HPV53 and HPV66 showed SCC/LSIL ratios of 0.02 and 0.01, respectively. HPV genotype distribution in LSIL differs from that in cervical cancer, highlighting the importance of HPV genotype in the risk of progression from LSIL to malignancy. Some regional differences in the relative importance of HPV genotypes in LSIL were noted.

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.

Background: Epigenetic mechanisms have been hypothesized to be etiologically involved in progression of cervical intraepithelial neoplasia (CIN) to invasive cervical cancer (ICC), although empirical data are lacking. Methods: We enrolled 148 controls, 38 CIN and 48 ICC cases at Kilimanjaro Christian Medical Centre from 2008-2009. HPV was genotyped by HPV linear array and HIV-1 serostatus was tested by two rapid HIV tests. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of IGF2/H19 and PEG1/MEST imprinted domains, using pyrosequencing. Logistic regression models were used to estimate odd ratios (ORs). Results: After adjusting for age, HPV infection, parity, hormonal contraceptive use, and HIV-1 serostatus, a 10% decrease in methylation at the IGF2 CTCF3 DMR was associated with a significantly higher risk of ICC (OR=2.00, 95% CI 1.14-3.44) and CIN (OR=1.51, 95% CI 1.00-2.50). We observed similar, albeit weaker pattern of associations between the H19 DMR and ICC and PEG1/MEST (OR= 1.51, 95% CI 0.90-2.53, and OR= 1.44, 95% CI 0.90-2.35, respectively). Restricting analyses to older women (>30 years old) further strengthened these associations. Conclusions: Aberrant DNA methylation at regulatory regions of imprinted genes may increase susceptibility to CIN and ICC and this association appears independent of HPV infection. While the small sample size limits inference, these findings support the hypothesis that DNA methylation at imprinted domains, including IGF2/H19 and PEG1/MEST, may represent susceptibility loci that can be exploited to identify, from among a large number of CIN, those likely to progress. Citation Format: Adriana C. Vidal, Monica Nye, Susan K. Murphy, Francine Overcash, Olola Oneko, John A. Bartlett, Zhiqing Huang, Pendo Mlay, Joseph Obure, Jennifer S. Smith, Brenda Hernandez, Cathrine Hoyo. IGF2/H19 and PEG1/MEST DNA methylation in CIN1, CIN2, CIN3 and cervical cancer in Tanzanian women: In search of disease progression biomarkers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A24.

Introduction: Metabotropic glutamate receptors are expressed throughout the central nervous system where they initiate a host of signaling events that regulate neuron function. We have identified the presence of metabotropic glutamate receptor 1 (mGluR1) in breast cancer cells and demonstrated a role for these receptors in regulating the pro-proliferative phenotype of these cells, both in vitro and in vivo. In this study, we investigate the signaling mechanism(s) by which mGluR1 mediates this pro-proliferative effect, as well as investigating a potential role for mGluR1 in mediating anti-apoptotic signaling events in triple negative breast cancer. Methods: We studied the effect of mGluR1 expression on cell growth using MDA-MB-231 cells stably transduced with plasmids expressing shRNA against GRM1, the gene coding for mGluR1 protein. Cell growth was measured by MTT assay and a role for mGluR1 in mediating apoptosis was assessed by measuring PARP cleavage products and Annexin V staining, using Riluzole or BAY36-7620 (BAY), non-competitive inhibitors of mGluR1 activity. To examine potential signaling mechanisms mediating cell growth, MDA-MB-231 cells were grown in glutamate-free media and stimulated with the mGluR1 agonist, L-Quisqualic acid, in the presence or absence of BAY. PKC and phosphorylated Akt levels were examined by Western analysis. Since mGluR1 is known to protect nerve cells from oxidative stress and increased oxidative stress can result in p53-induced apoptosis, we measured the effect of Riluzole on p53 expression and oxidative stress levels in MDA-MB-231 cells. Oxidative stress was measured using immunofluorescent staining with carboxy-H2DCFDA and p53 by Western blot analysis. Results: MDA-MB-231 cells were transduced with Lentiviral constructs expressing shRNA against GRM1 and cell growth assessed by MTT assay. Growth of these cells was inhibited 50% by shRNA against GRM1 compared to non-silencing scrambled control. In addition, inhibition of mGluR1 activity by BAY in MDA-MB-231 cells prevented signaling through Akt which ultimately resulted in increased p53 expression and superoxide production and apoptosis. Incubation of MDA-MB-231 or BT549 cells with varying doses of Riluzole resulted in increased PARP cleavage by 24 hours. FACS analysis also showed a three- and ten-fold increase in Annexin V staining of MDA-MB-231 cells after 24 and 48 hr incubation with Riluzole, respectively. BAY also induced Annexin V staining of these cells by almost 3-fold at the 48 hr timepoint. Conclusion: Our results showing that inhibition of mGluR1 inhibits proliferation and increases apoptosis and oxidative stress implicate mGluR1, or one of its downstream signaling molecules, as potential new molecular targets for the treatment of breast cancer. Because it is an FDA-approved oral drug with low toxicity, Riluzole represents a promising approach in the treatment of triple negative breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1673. doi:10.1158/1538-7445.AM2011-1673

Introduction: Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity and feedback inhibition of neurotransmitter release. However, recent studies suggest that these receptors are also present and functional in various cancer types, including melanoma and prostate cancer cells. In addition, brain endothelial cells were recently shown to express mGluR1 receptors and to mediate VEGF-induced endothelial cell proliferation both in vivo and in vitro. These results suggest a role for mGluR1 in mediating angiogenesis, a process that is required for cancer tumors to grow and metastasize. Both VEGF levels and angiogenesis are independent prognostic indicators in primary breast cancer patients with their presence being associated with early relapse. Therefore, we wished to examine a potential role for mGluR1 in mediating VEGF-induced breast cancer tumor progression. Methods: To do this, we analyzed several breast cancer cell lines as well as primary endothelial cells for mGluR1 protein and mRNA expression and looked at their potential role in mediating cell growth, angiogenesis and tumor formation in a mouse xenograph model. The role of mGluR1 on cell growth was determined using an MTT assay and by counting isolated nuclei with a Coulter counter in the presence and absence of BAY36-7620 and Riluzole, specific non-competitive inhibitors of mGluR1. The angiogenic potential of endothelial cells and the role of mGluR1 in mediating this process were measured using a matrigel tube formation assay in the presence and absence of BAY36-7620 and Riluzole. Lastly, the effect of mGluR1 on tumor formation and angiogenesis in vivo was determined by measuring tumor growth and blood vessel formation in a xenograft model derived from cell lines expressing high levels of mGluR1 and treated with either the mGluR1 inhibitors or vehicle. Results: The results of this study show strong mRNA and protein expression of mGluR1 in several breast cancer cell lines as well as in HUVECs and human dermal micro-endothelial cells (HDMEC). Cell growth, in the presence of either BAY36-7620 or Riluzole, inhibited cell growth in all these cells in a dose-response manner and completely inhibited VEGF-induced matrigel tube formation of HUVECs and HDMEC. In addition, tumor growth in a xenograft model using MBA231 cells, which expressed high levels of mGluR1, was inhibited by 30% and 50% in the presence of 9 mg/kg and 18 mg/kg Riluzole, respectively. Conclusion: By inhibiting both breast cancer cell growth and angiogenesis, these results implicate mGluR1 as a major player in the development and progression of breast cancer and thus suggests that mGluR1 may serve as a useful therapeutic target in the treatment of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1578.