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Oxylipins derived from arachidonic acid (ARA) have been implicated in the development of colorectal adenomas and colorectal cancer. The primary purpose of this work was to determine the relationship between plasma levels of oxylipins and colorectal adenoma characteristics at study entry, as well as with the development of a new adenoma during follow-up within a Phase III adenoma prevention clinical trial with selenium (Sel). Secondarily, we sought to determine whether the selenium intervention influenced plasma oxylipin levels. Four oxylipins were quantified in stored plasma samples from a subset of Sel study subjects (n = 256) at baseline and at 12-months. There were significantly lower odds of an advanced adenoma at baseline with higher prostaglandin E2 (PGE2), with an OR (95% CI) of 0.55 (0.33–0.92), and with 5-hydroxyeicosatetraenoic acid (5-HETE) ((0.53 (0.33–0.94)), and of a large adenoma with higher PGE2 ((0.52 (0.31–0.87)). In contrast, no associations were observed between any oxylipin and the development of a new adenoma during follow-up. Selenium supplementation was associated with a significantly smaller increase in 5-HETE after 12 months compared to the placebo, though no other results were statistically significant. The ARA-derived oxylipins may have a role in the progression of non-advanced adenoma to advanced, but not with the development of a new adenoma.

Background Human papillomavirus (HPV) vaccines are indicated for the prevention of cancers and genital warts caused by vaccine-covered HPV types. Although the standard regimen requires a two or three-dose vaccine series, there is emerging data suggesting that a single dose of the bivalent or quadrivalent HPV vaccine generates persistently positive antibody titers. No similar data is yet available for the nonavalent HPV vaccine, currently the only HPV vaccine available in the United States. The overall objective of our study is to assess the stability and kinetics of antibody titers for 24 months following a single dose of the nonavalent HPV vaccine among preteen girls and boys. Methods This is a prospective, single-arm, open-label, non-randomized, Phase IIa trial among 9–11 year-old girls and boys to determine the immunogenicity after a single dose of the nonavalent HPV vaccine (GARDASIL® 9) over 24 months, with a deferred booster dose at 24 months and an optional booster at 30 months after the first dose. Participants provide blood specimens at 6, 12, 18, 24, and 30 months after the first dose. Serologic geometric mean titers (GMT) of the nine vaccine types (HPV 16/18/ 6/11/31/33/45/52/58) will be measured at each time point. The primary objective is to determine the stability of type-specific serologic GMT of HPV16 and HPV18 between the 6- vs. 12-month, 12- vs. 18-month, and 18- vs. 24-month visits. Secondary objectives are to determine the stability of type-specific serologic GMT of the other HPV types (HPV 6/11/31/33/45/52/58) between the visits and to assess safety and reactogenicity after each vaccine dose. Discussion Single dose HPV vaccination could simplify the logistics and reduce costs of HPV vaccination in the US and across the world. This study will contribute important immunogenicity data on the stability and kinetics of type-specific antibody titers and inform feasibility of the single dose HPV vaccination paradigm. Trial registration ClinicalTrials.gov Identifier: NCT02568566. Registered on October 6, 2015. Electronic supplementary material The online version of this article (10.1186/s12885-019-5444-4) contains supplementary material, which is available to authorized users.

PURPOSE: Obesity is a known risk factor for post-menopausal breast cancer and may increase risk for triple negative breast cancer in premenopausal women. Intervention strategies are clearly needed to reduce obesity-associated breast cancer risk. METHODS: We conducted a Phase II double-blind, randomized, placebo-controlled trial of metformin in overweight/obese premenopausal women with components of metabolic syndrome to assess the potential of metformin for primary breast cancer prevention. Eligible participants were randomized to receive metformin (850 mg BID, n = 76) or placebo (n = 75) for 12 months. Outcomes included breast density, assessed by fat/water MRI with change in percent breast density as the primary endpoint, anthropometric measures, and intervention feasibility. RESULTS: Seventy-six percent in the metformin arm and 83% in the placebo arm (p = 0.182) completed the 12-month intervention. Adherence to study agent was high with more than 80% of participants taking ≥80% assigned pills. The most common adverse events reported in the metformin arm were gastrointestinal in nature and subsided over time. Compared to placebo, metformin intervention led to a significant reduction in waist circumference (p

Purpose: To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer. Experimental Design: An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor–positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy. Results: In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), −14.6 to −4.7] at 12 months, an absolute decrease of −1.4% (95% CI, −2.5 to −0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40). Conclusions: This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.

BACKGROUND The aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention. METHODS Individuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3–12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing. RESULTS Twenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses (P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological (P = 0.04) and clinical (P = 0.01) responses. CONCLUSION To our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent. TRIAL REGISTRATION NCT02581137 FUNDING NIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870

A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, double-blinded study in current heavy smokers to compare modulating effects of intermittent versus continuous low-dose ASA on nasal epithelium gene expression and arachidonic acid (ARA) metabolism. Fifty-four participants were randomized to intermittent (ASA 81 mg daily for one week/placebo for one week) or continuous (ASA 81 mg daily) for 12 weeks. Low-dose ASA suppressed urinary prostaglandin E2 metabolite (PGEM; change of −4.55 ± 11.52 from baseline 15.44 ± 13.79 ng/mg creatinine for arms combined, P = 0.02), a surrogate of COX-mediated ARA metabolism, but had minimal effects on nasal gene expression of nasal or bronchial gene-expression signatures associated with smoking, lung cancer, and chronic obstructive pulmonary disease. Suppression of urinary PGEM correlated with favorable changes in a smoking-associated gene signature (P < 0.01). Gene set enrichment analysis (GSEA) showed that ASA intervention led to 1,079 enriched gene sets from the Canonical Pathways within the Molecular Signatures Database. In conclusion, low-dose ASA had minimal effects on known carcinogenesis gene signatures in nasal epithelium of current smokers but results in wide-ranging genomic changes in the nasal epithelium, demonstrating utility of nasal brushings as a surrogate to measure gene-expression responses to chemoprevention. PGEM may serve as a marker for smoking-associated gene-expression changes and systemic inflammation. Future studies should focus on NSAIDs or agent combinations with broader inhibition of pro-inflammatory ARA metabolism to shift gene signatures in an anti-carcinogenic direction.

Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokersJulie E. Bauman, Chiu-Hsieh Hsu, Sara Centuori, Jose Guillen-Rodriguez, Linda Garland, Emily Ho, Lisa Bengtson, Malgorzata Wojtowicz, Eva Szabo, H-H Sherry ChowIntroduction: Diets high in cruciferous vegetables are associated with reduced risk of tobacco-related cancers. Crucifers are rich in the phytochemical glucoraphanin (GR), which is hydrolyzed by myrosinase to its bioactive form, sulforaphane (SF). SF upregulates the NRF2 transcription factor and downstream target genes in the antioxidant response element. As GR is concentrated in broccoli seeds relative to mature plants, broccoli seed preparations (BSP) are under development as chemopreventive agents. BSP increased detoxication of air pollutants including benzene in Qidong, China. Methods: We conducted a randomized crossover trial evaluating the detoxication of benzene and other tobacco carcinogens by the BSP Avmacol, tablets comprised of broccoli seed powder and broccoli sprout extract, in otherwise healthy smokers (≥ 20 pack-years). Each subject was treated with low and high dose BSP (70 vs. 140 GR equivalents daily for 2 weeks), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxication of benzene, measured by change in urinary excretion of its mercapturic acid metabolite (S-phenyl mercapturic acid, SPMA). Secondary endpoints included detoxication of the carcinogens acrolein and crotonaldehyde, and SF bioavailability assessed by urinary SF metabolites.Results: 49 subjects were randomized from Feb 2018-Nov 2019: 26 female, mean age 56.3. Treatment-related adverse events (AE) were gastrointestinal; most common were grade 1-2 bloating/cramping/abdominal pain (11; 22%), grade 1 diarrhea (11; 22%), grade 1 flatulence (10; 20%). No grade ≥ 3 AE were observed. One subject withdrew after unrelated AE. Compliance with BSP and biomarker measurements was 98%. Primary and secondary endpoints are presented in the Table. Conclusion: The BSP Avmacol was bioavailable as SF metabolites and significantly increased the acute detoxication products of benzene and acrolein in heavy smokers. Dose LevelChange in Metabolite (IQR)a; N=48P-ValueΔ SF MetabolitesbLow Dose19.93 (6.50, 49.00) nmol/mg Cr Citation Format: Julie E. Bauman, Chiu-Hsieh Hsu, Sara Centuori, Jose Guillen-Rodriguez, Linda Garland, Emily Ho, Lisa Bengtson, Malgorzata Wojtowicz, Eva Szabo, H-H Sherry Chow. Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB221.

Background: The effect of intrinsic and extrinsic factors (e.g. the environment and genetics) on the metabolome may have implications for disease risk, health disparities, and effectiveness of clinical interventions. Purpose: This study investigated whether plasma metabolomic profiles differ between U.S. born and foreign-born Hispanics participating in a weight loss intervention. Secondarily, we sought to examine if country of origin had an effect on the intervention effectiveness. Methods: Participants were overweight and obese Hispanic men (N=42) aged 18 to 64 years enrolled in a 24-week weight loss intervention. Metabolomic profiles were acquired from plasma using ultra performance liquid chromatography-mass spectroscopy (UPLC-MS) at baseline, 12 and 24 weeks. Models were visualized using supervised orthogonal projections to latent structures-discriminant analysis (OPLS-DA); R2X cut points of 0.75, 0.50, and 0.25 were used to describe substantial, moderate, or weak levels of predictive accuracy, respectively. Score plots (S-plots) were utilized to select metabolites that influenced the OPLS-DA model. Progenesis QI was used for peak integration and metabolite identification in addition to the Human Metabolite Data Base (HMDB). The effect of place of birth on weight loss was examined using multiple linear regression. Results: Foreign-born participants were older (P = 0.0086), had less education (P < 0.001), were mostly Spanish-preferred speakers (P < 0.001), and had less acculturation (P < 0.001) compared to U.S. born participants. The metabolome between U.S. born vs foreign-born were moderately (R2X =0.65), weakly (R2X= 0.33), and substantially (R2X =0.79) different at baseline, 12 weeks, and 24 weeks. Endogenous metabolites such as alpha-keto and amino acids, phospholipids, fatty acids, as well as some dietary compounds were characteristic of the foreign-born participants, but not the U.S. born, at baseline. Post-intervention, metabolites from dietary sources (cereals, herbs and spices, mushrooms, chives, onions, and beer), and lipids (diacylglycerols, cholesteryl and glycerolipids) where characteristic of the foreign-born group, whereas saponins and metabolites from green vegetables, avocados, alcoholic beverages, coffee, and green tea were characteristic of the U.S. born group. Models comparing study arm or weight loss status were weak. At 24 weeks, U.S. born participants had more weight loss than foreign born (P = 0.023). Conclusion: Plasma metabolomic profiles from Hispanic men differ by country of origin. Analyses to determine whether the greater intervention benefit among U.S. born Hispanic males can be explained by their baseline metabolome are pending. Future studies should determine factors that influence differences in metabolomic profiles in order to tailor interventions. Citation Format: Melissa Lopez-Pentecost, David O. Garcia, Xiaoxiao Sun, Cynthia A. Thomson, H-H. Sherry Chow, Wade M. Chew, Jessica A. Martinez. Place of birth influences the metabolomic profile and preliminary effectiveness of a weight loss intervention among Hispanic men from the ANIMO pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2352.

Leda Gattoc,1 Paula M Frew,2–4 Shontell N Thomas,5 Kirk A Easley,6 Laura Ward,6 H-H Sherry Chow,7 Chiemi A Ura,8 Lisa Flowers8 1Division of Gynecologic Oncology, Wayne State University, Detroit, MI, 2Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 3Department of Behavioral Sciences and Health Education, 4Hubert Department of Global Health, 5Ochsner Medical Center, Kenner, LA, 6Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, 7Department of Medicine, University of Arizona, Tucson, AZ, 8Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Emory University School of Medicine, Atlanta GA, USA Background: This is a Phase I trial demonstrating safety and tolerability of intravaginal curcumin for future use in women with cervical neoplasia.Objective: The objective of this study was to assess the safety, tolerability, and pharmacokinetics of intravaginal curcumin in healthy women. Study design: We conducted a 3+3 dose-escalation Phase I trial in a group of women aged 18–45years. Thirteen subjects were given one of four doses of curcumin powder (500mg, 1,000mg, 1,500mg, and 2,000mg) packed in gelatin capsules, which was administered intravaginally daily for 14days. The primary end point for this study was safety based on severe adverse events regarding laboratory toxicity, clinical findings, and colposcopic abnormalities. We administered an acceptability questionnaire to assess product experience and attributes. Results: No dose-limiting toxicities (0/13) were experienced (95% confidence interval: 0.0%–22.8%) in this study. The pharmacokinetics data demonstrated that curcumin and curcumin conjugates were not measurable in the serum and negligible in the urine of the study participants. Although 23 adverse events occurred during the course of the trial, all events were grade I based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and were resolved by the end of the study in an average of 9days. Fifty-six percent of the adverse events were related to the study drug, which included genital pruritus (23% of subjects), vaginal discharge (100%), vaginal dryness (15%), abnormal prothrombin (23%), and hypokalemia (8%). Conclusion: Intravaginal curcumin was well tolerated by all subjects and safe. In this Phase I trial, there were no severe adverse events observed at any of the administered dose levels. All adverse events were grade I and did not result in early termination of the study. There was no evidence of systemic absorption or significant local absorption of intravaginally administered curcumin. Keywords: cervix, curcumin, intravaginal, safety, tolerability, neoplasia

Background Androgen deprivation therapy (ADT) for prostate cancer is associated with adverse cardiometabolic effects such as reduced libido, hot flashes, metabolic syndrome, diabetes, myocardial infarction, and stroke. This reduces quality of life and potentially increases mortality. Several large clinical trials have demonstrated improvements in cardiometabolic risk with comprehensive multimodality lifestyle modification. However, there is a lack of data for such interventions in men on ADT for prostate cancer, and existing studies have used non-standardized interventions or lacked data on metabolic risk factors. Objective The Comprehensive Lifestyle Improvement Project for Prostate Cancer (CLIPP) is designed to address these gaps by using an intervention modeled on the Diabetes Prevention Program, a standardized multicomponent intervention with demonstrated effectiveness in reducing cardiometabolic risk factors that has been successfully adapted for multiple disease types including breast cancer. Methods A single-arm unblinded clinical trial will be conducted to determine the feasibility of conducting a 24-week comprehensive lifestyle modification intervention that targets weight loss and increased physical activity modeled on the Diabetes Prevention Program in 30 men on ADT for prostate cancer. Secondary aims are to determine the effect of the intervention on cardiometabolic markers and quality of life. The tertiary aim is to determine the effect of the intervention on markers of inflammation and angiogenesis, important mechanisms for prostate cancer progression. Participants will be recruited from the University of Arizona Cancer Center and the surrounding community. The intervention will be delivered weekly in person and over the phone for 16 weeks. For Weeks 16-24, participants receive weekly phone calls from the study health coach to motivate them to continue their lifestyle modification. Questionnaire and biological data are collected at baseline, 12 weeks, and 24 weeks. Body composition using dual-energy x-ray absorptiometry scans will be performed at baseline and end of study. Results Based on a sample size of 30, the two-sided 95% confidence interval will not be wider than 0.373 standard deviations for the adherence rate and will not be wider than 0.374 for the retention rate. In addition, the study will have a power of 80% to detect a change of 0.47 standard deviations from baseline for each of the markers investigated in the secondary and tertiary aims assuming a within-subject correlation of 0.20 at a significance level of 5%. The recruitment period is from October 2018 to April 2019. Conclusions The aim of CLIPP is to determine the feasibility of conducting a Diabetes Prevention Program–style comprehensive lifestyle modification intervention in men with ADT for prostate cancer and its effects on cardiometabolic adverse effects, quality of life, as well as markers of inflammation and angiogenesis. Results will inform the development of future clinical trials in this population. International Registered Report Identifier (IRRID) DERR1-10.2196/12579

ObjectiveWhile controversial, observational and randomized clinical trial data implicate the micronutrient selenium (Se) in the development of type 2 diabetes (T2D). The aim of this study was to test the hypothesis that Se supplementation adversely affects pancreatic β-cell function and insulin sensitivity.Research design and methodsIn a subset of 400 individuals participating in a randomized, placebo-controlled trial of Se at 200 µg/day for colorectal adenomatous polyps, fasting plasma glucose and insulin were measured before randomization and within 6 months of completing intervention. Change in the homeostasis model assessment-β cell function (HOMA2-%β) and insulin sensitivity (HOMA2-%S) were compared between arms. A subgroup of 175 (79 Se and 96 placebo) participants underwent a modified oral glucose tolerance test (mOGTT) at the end of intervention and change in glucose values was assessed.ResultsNo statistically significant differences were observed for changes in HOMA2-%β or HOMA2-%S between those who received Se compared with placebo. After a mean of 2.9 years on study, mean HOMA2-%β values were 3.1±24.0 and 3.1±29.8 for the Se and placebo groups, respectively (p=0.99). For HOMA2-%S, the values were −0.5±223.2 and 80.9±1530.9 for the Se and placebo groups, respectively (p=1.00). Stratification by sex or age did not reveal any statistically significant effects on insulin sensitivity by treatment group. For mOGTT, mean baseline fasting blood glucose concentrations were significantly higher among participants in the placebo group compared with the Se group (96.6±14.6 and 92.3±12.0, respectively; p=0.04), a trend which remained through the 20 min assessment.ConclusionsThese findings do not support a significant adverse effect of daily Se supplementation with 200 µg/day of selenized yeast on β-cell function or insulin sensitivity as an explanation for previously reported associations between Se and T2D. Further clarification of longer term effects of Se is needed.Clinical trial registryNIH Clinical Trials.gov numberNCT00078897.

BACKGROUND: Selenium, an essential trace element, has been investigated as a potential cancer prevention agent. However, several studies have indicated that selenium supplementation may be associated with an increased risk of type 2 diabetes (T2D), although an equivocal relation of this nature requires confirmation. OBJECTIVE: We examined the association between baseline plasma concentrations of selenium and the prevalence of T2D, as well as whether participant characteristics or intake of other antioxidant nutrients modified this relation. METHODS: We conducted cross-sectional analyses of 1727 participants from the Selenium Trial, a randomized clinical trial of selenium supplementation for colorectal adenoma chemoprevention that had data for baseline selenium plasma concentrations, T2D status, and dietary intake. Logistic regression modeling was used to evaluate the associations between plasma selenium concentrations and prevalent T2D, adjusting for confounding factors. Heterogeneity of effect by participant characteristics was evaluated utilizing likelihood-ratio tests. RESULTS: Mean ± SD plasma selenium concentrations for those with T2D compared with those without T2D were 143.6 ± 28.9 and 138.7 ± 27.2 ng/mL, respectively. After adjustment for confounding, higher plasma selenium concentrations were associated with a higher prevalence of T2D, with ORs (95% CIs) of 1.25 (0.80, 1.95) and 1.77 (1.16, 2.71) for the second and third tertiles of plasma selenium, respectively, compared with the lowest tertile (P-trend = 0.007). No significant effect modification was observed for age, sex, body mass index, smoking, or ethnicity. Increased odds of T2D were seen among those who were in the highest tertile of plasma selenium and the highest category of intake of β-cryptoxanthin (P-trend = 0.03) and lycopene (P-trend = 0.008); however, interaction terms were not significant. CONCLUSIONS: These findings show that higher plasma concentrations of selenium were significantly associated with prevalent T2D among participants in a selenium supplementation trial. Future work is needed to elucidate whether there are individual characteristics, such as blood concentrations of other antioxidants, which may influence this relation.

Background: Although breast cancer (BC) may occur at any age, its prevalence is greater postmenopause. Greater than 75 % of postmenopausal BCs are hormone dependent. Aromatase inhibitors suppress postmenopausal estrogen biosynthesis. Letrozole has demonstrated efficacy against BC in the adjuvant and metastatic setting at the treatment dose of 2.5 mg daily. Its potential role in BC prevention has been inferred from reductions in contralateral BCs. Its side effect profile, similar to other AIs, includes exacerbation of menopausal symptoms that negatively impact quality of life (QOL) and may result in discontinuation of the drug. Both anastrazole and exemestane have been demonstrated to reduce BC in high-risk women. Hypothesis: Lower and intermittent doses of letrozole effectively suppress estrogen in the high-risk postmenopausal woman and provide a better side effect profile. Methods: A randomized, double-blind study comparing the impact of varying letrozole doses (2.5 mg daily, 2.5 mg MWF, 1.0 mg MWF, or 0.25 mg MWF) on estrogen suppression and side effects--lipids, bone resorption, menopause, and QOL-- was conducted. Participants randomized to intermittent dosing received placebo on nontreatment days. Results: 112 participants were enrolled at 2 clinical sites. Mean patient age was 62.8 years, and average BMI was 29.8. Analysis of available data after 24 weeks of therapy revealed statistically significant increase in triglycerides (N=94): 114.67±48.39 to 125.79±54.31 (p Conclusions: De-escalating doses of letrozole suppress postmenopausal estrogen effectively and result in statistically significant increases in triglycerides, C-telopeptide and vasomotor symptoms without impact on QOL. Presentation will include unblinded intervention arm outcomes. Citation Format: Ana Maria Lopez, Hsiao Hui Sherry Chow, Denise Frank, Sandhya Puthi, Judy Boughey, Paul Hsu, Jose Guillen, Marjorie Perloff, Michelle Ley, Julie E Lang. De-escalating doses of letrozole in post menopausal women at high risk for breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-12-04.

Background: The effect on tea consumption on blood pressure and liver enzymes are controversial. The beneficial effects of long-term ingestion of black and green tea on systolic and diastolic blood pressure have been suggested by several studies.Objectives: The overall goal of this study was to determine the effects of high tea consumption on blood pressure and liver enzymes.Design: We completed a 6-month randomized, controlled, double-blinded trial in a group of former and current smokers who were randomized to receive black or green tea preparations or a matching placebo.Results: A total of 146 participants (80 females and 66 males) were enrolled in the study. At the end of the 6-month intervention, women in the black tea group showed a 4 mmHg decrease (p = 0.01) in systolic blood pressure while female in the green tea group showed a 30.1% decrease (p = 0.035) in Alanine transaminase (ALT). No significant changes were observed in men.Conclusion: Our data confirm previous findings related to the beneficial effect of black tea on blood pressure and of green tea on serum liver enzymes especially among females. In addition, our study showed that long-term regular consumption of black tea and green is safe.

Background. The level of systemic inflammation as measured by circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6) is linked to an increased risk for cardiovascular diseases (CVD) and cancer.Methods. We recruited 154 current and former smokers between 40 and 80 years of age with 25 or more pack-years of smoking history to study the relationship between inflammatory markers (CRP and IL-6) and smoking status.Results. Our results show that male smokers had significantly higher levels of serum IL-6 compared to male former smokers. We did not find any gender specific differences for smoking and CRP levels but the IL-6 levels were slightly lower in females compared to males. Additionally, our results show that CRP is significantly associated with IL-6 regardless of smoking status. Modelling indicates that the significant predictors of CRP levels were biomarkers of the metabolic syndrome while the significant predictors of IL-6 levels were age and plasma triglycerides among former smokers and the numbers of smoked packs of cigarettes per year among smokers.Conclusions. In conclusion, our study showed that CRP levels were not associated with markers of smoking intensity. However, IL-6 levels were significantly associated with smoking especially among current smokers.

Metformin has recently been shown to have potential to reduce prostate cancer risk. We conducted a randomized, double-blind, placebo-controlled trial to determine the modulating effects of metformin on tissue and systemic biomarkers of drug activity and its distribution into the prostate tissue. Twenty patients with prostate cancer scheduled to undergo prostatectomy were randomly assigned to receive either extended-release metformin or placebo for a median of 34 days before surgery. Prostatectomy and serum samples were analyzed for metformin concentrations, serum biomarkers of drug activity (prostate-specific antigen, insulin, insulin-like growth factor-1, insulin-like growth factor binding protein 3, sex hormone-binding globulin, and testosterone) and tissue biomarkers of proliferation, apoptosis, cell cycle regulation, and mTOR inhibition. For participants in the metformin arm, the prostate tissue and serum metformin concentrations ranged from 0.88 to 51.2 μg/g tissue and from not detectable to 3.6 μg/ml, respectively. There were no differences between the two groups in either the postintervention tissue biomarker expression in the prostatectomy tissue or pre to postintervention changes in serum biomarkers. We conclude that metformin distributes to human prostate tissue, suggesting that metformin could exert its effects directly on tissue targets. However, there was no difference in tissue and systemic drug effect biomarkers between the two treatment arms. Future studies with longer intervention duration and larger sample size should be considered in order to evaluate the potential of metformin for prostate cancer prevention.

Diindolylmethane (DIM), a bioactive metabolite of indole-3-carbinol found in cruciferous vegetables, has proposed cancer chemoprevention activity in the breast. There is limited evidence of clinically relevant activity of DIM or long-term safety data of its regular use. A randomized, double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined use of BioResponse DIM® (BR-DIM) with tamoxifen. Women prescribed tamoxifen (n = 130) were randomly assigned oral BR-DIM at 150 mg twice daily or placebo, for 12 months. The primary study endpoint was change in urinary 2/16α-hydroxyestrone (2/16α-OHE1) ratio. Changes in 4-hydroxyestrone (4-OHE1), serum estrogens, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites were assessed. Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. BR-DIM increased the 2/16α-OHE1 ratio (+3.2 [0.8, 8.4]) compared to placebo (−0.7 [−1.7, 0.8], P

Objective In vitro data and pilot data suggest that green tea catechins may possess chemopreventive activity for cervical cancer and precursor lesions. We conducted a randomized, double-blind, placebo-controlled trial of Polyphenon E (decaffeinated and enriched green tea catechin extract) in women with persistent human papillomavirus (HPV) infection and low-grade cervical intraepithelial neoplasia (CIN1) to evaluate the potential of Polyphenon E for cervical cancer prevention. Methods Ninety-eight eligible women were randomized to receive either Polyphenon E (containing 800mg epigallocatechin gallate) or placebo once daily for 4 months. The primary study outcome was oncogenic HPV clearance and clearance of CIN1. Results Polyphenon E was shown to be acceptable, safe and well tolerated. There was no difference in the response rate by treatment allocation. Complete response, defined as negative for high-risk HPV and normal histopathology, was noted in 7 (17.1%) and 6 (14.6%) women in the Polyphenon E and placebo arms, respectively. Progression, defined as persistent oncogenic HPV with histopathologic evidence of progression, was more common in the Polyphenon E group than in the placebo group [6 (14.6%) vs. 3 (7.7%)]. Conclusion Based on the largest randomized placebo-controlled trial of a green tea extract for HPV related cervical disease, we conclude that 4months of Polyphenon E intervention did not promote the clearance of persistent high-risk HPV and related CIN1. Further studies may be necessary to better delineate the risk factors for persistent HPV infection and biology of the disease to facilitate the evaluation of chemopreventive strategies.

Background Selenium supplementation may help to prevent colorectal cancer; as precursors of colorectal cancer, colorectal adenomas are a surrogate for colorectal cancer. Selenium supplementation may increase risk of type 2 diabetes (T2D). Methods The Selenium and Celecoxib (Sel/Cel) Trial was a randomized, placebo controlled trial of selenium 200 µg daily as selenized yeast and celecoxib 400 mg once daily, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of colorectal adenomas. The primary outcome was adenoma development. Celecoxib was suspended because of cardiovascular toxicity in other trials, but accrual continued to selenium and placebo. A total of 1621 participants were randomly assigned to selenium or placebo, of whom 1374 (84.8%) were available for analysis. All statistical tests were two-sided. Results In the respective placebo and selenium arms of 689 and 685 participants, adenoma detection after medians of 33.6 (range = 0.0-85.1 months) and 33.0 months (range = 0.0-82.6 months) were 42.8% and 44.1% (relative risk [RR] = 1.03, 95% confidence interval [CI] = 0.91 to 1.16, P = .68). In participants with baseline advanced adenomas, adenoma recurrence was reduced by 18% with selenium (RR = 0.82, 95% CI = 0.71 to 0.96, P = .01). In participants receiving selenium, the hazard ratio for new-onset T2D was 1.25 (95% CI = 0.74 to 2.11, P = .41), with a statistically significantly increased risk of selenium-associated T2D among older participants (RR = 2.21; 95% CI = 1.04 to 4.67, P = .03). Conclusions Overall, selenium did not prevent colorectal adenomas and showed only modest benefit in patients with baseline advanced adenomas. With limited benefit and similar increases in T2D to other trials, selenium is not recommended for preventing colorectal adenomas in selenium-replete individuals.

Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk. This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored. The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases. ClinicalTrials.gov Identifier: NCT02028221 . Registered on January 2, 2014. Grant #: 1R01CA172444-01A1 awarded on Sept 11, 2013.

COX inhibitors reduce colorectal adenoma recurrence by up to 45% and selenium supplementation may prevent colorectal cancer. Following colonoscopic adenoma resection, 1,600 men and women, ages 40 to 80 years, were randomized to celecoxib (400 mg daily), a selective COX-2 inhibitor, and/or selenium (200 μg daily as selenized yeast), or double placebo. The trial was initiated in November 2001. The primary trial endpoint is adenoma recurrence in each intervention group compared with placebo, as determined by surveillance colonoscopy conducted three to five years after baseline. Randomization was stratified by use of low-dose aspirin (81 mg) and clinic site. Following reports of cardiovascular toxicity associated with COX-2 inhibitors, the celecoxib arm was discontinued in December 2004 when 824 participants had been randomized. Accrual continued with randomization to selenium alone or placebo. Randomization of the originally planned cohort (n = 1,621) was completed in November 2008. A further 200 patients with one or more advanced adenomas (denoting increased risk for colorectal cancer) were accrued to enhance statistical power for determining intervention efficacy in this higher-risk subgroup. Accrual of the total cohort (n = 1,824) was completed in January 2011. Baseline cohort characteristics include: mean age 62.9 years; 65% male; body mass index (BMI) 29.1 ± 5.1; 47% taking low-dose aspirin while on trial; 20% with three or more adenomas; and 38% with advanced adenomas. Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type II diabetes will also be reported. Cancer Prev Res; 5(12); 1381–93. ©2012 AACR.

Purpose: This phase I trial evaluated intraperitoneal (i.p.) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. Experimental Design: Dose escalation of day 1 i.p. pemetrexed accrued three patients to each of five dose levels (60–1,000 mg/m2), along with day 2 i.p. cisplatin (75 mg/m2) and day 8 i.p. paclitaxel (60 mg/m2). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics of i.p. pemetrexed. Results: Cycles, given every 21 days, had an 80% 6-cycle completion rate. There was minimal grade III toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, two of three patients experienced ≥grade III and dose-limiting toxicity (DLT; hematologic, infection, gastrointestinal). There was a pharmacokinetic advantage for i.p. pemetrexed with an intraperitoneal:plasma area under the concentration–time curve ratio of 13-fold. Neither analysis of pharmacokinetic nor homocysteine levels explains the unexpected severity of toxicity in those two patients. On the basis of plasma C24h levels, the 42 cycles at ≥500 mg/m2 i.p. pemetrexed without DLT, the MTD appears to be 500 mg/m2. Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months). Conclusions: This i.p.-only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with i.p. pemetrexed at 500 mg/m2. The favorable toxicity profile at doses

Background: Limonene, a major component in citrus oil, has demonstrated anti-cancer effects in preclinical mammary cancer models. However, the effective oral dose translates to a human dose that may not be feasible for chronic dosing. We proposed to evaluate topical application of limonene to the breast as an alternative dosing strategy. Materials and Methods: We conducted a mouse disposition study to determine whether limonene would be bioavailable in the mammary tissue after topical application. SKH-1 mice received topical or oral administration of limonene in the form of orange oil every day for 4 weeks. Plasma and mammary pads were collected 4 hrs after the final dosing. We also conducted an exploratory clinical study to evaluate the safety and feasibility of topically applied limonene in the form of orange oil to the breast. Healthy women were recruited to apply orange oil containing massage oil to their breasts daily for four weeks. Safety and feasibility were assessed by reported adverse events, clinical labs, and usage compliance. Pre and post-intervention nipple aspirate fluid (NAF) and plasma were collected for limonene concentration determination. Results: The mouse disposition study showed that topical and oral orange oil administration resulted in similar mammary tissue disposition of limonene with no clinical signs of toxicity. In the clinical study, the topical application of limonene containing massage oil to the breast was found to be safe with high levels of usage compliance for daily application, although NAF and plasma limonene concentrations were not significantly changed after the massage oil application. Conclusions: Our studies showed that limonene is bioavailable in mammary tissue after topical orange oil application in mice and this novel route of administration to the breast is safe and feasible in healthy women.

Although limited, observations from cell culture, animal, and epidemiological studies support the presence of anti-cancer properties in citrus peel and the primary bioactive food constituent, d-limonene. Early evidence from animal models suggests that when ingested, d-limonene exhibits a wide spectrum of biologic activity including chemotherapeutic and chemopreventive effects. In some of these early models, an analog of d-limonene, perillyl alcohol, demonstrated a more potent effect than d-limonene itself. Yet, when perillyl alcohol advanced to clinical trials, several trials were ended early due to doselimiting toxicities. Alternatively, oral d-limonene administration in humans is well tolerated even at high doses supporting its investigation as a potential bioactive for cancer prevention. Though the exact mechanisms of action of d-limonene are unclear, immune modulation and antiproliferative effects are commonly reported. Here, we review the pre-clinical evidence for d-limonene’s anticancer mechanisms, bioavailability, and safety, as well as the evidence for anti-cancer effects in humans, focusing on studies relevant to its use in the prevention and treatment of breast cancer.

Several studies have investigated the potential role of selenium (Se) in the development of type 2 diabetes (T2D) with disparate findings. We conducted a systematic review and meta-analysis to synthesize the evidence of any association between Se and T2D. PubMed, Embase, and Scopus were searched following the Preferred Reporting Items for Systematic Reviews and Meta-analysis Approach (PRISMA). Sixteen studies from 15 papers met inclusion criteria defined for this review. Of the 13 observational studies included, 8 demonstrated a statistically significant positive association between concentrations of Se and odds for T2D, with odds ratios (95% confidence intervals) ranging from 1.52 (1.01⁻2.28) to 7.64 (3.34⁻17.46), and a summary odds ratio (OR) (95% confidence interval (CI)) of 2.03 (1.51⁻2.72). In contrast, among randomized clinical trials (RCTs) of Se, a higher risk of T2D was not observed for those who received Se compared to a placebo (OR = 1.18, 95% CI 0.95⁻1.47). Taken together, the results for the relationship between Se and T2D differ between observational studies and randomized clinical trials (RCTs). It remains unclear whether these differences are the result of uncontrolled confounding in the observational studies, or whether there is a modest effect of Se on the risk for T2D that may vary by duration of exposure. Further investigations on the effects of Se on glucose metabolism are needed.

Despite encouraging recent results from novel treatment options, such as immunotherapy, for head and neck squamous cell carcinoma (HNSCC), limited progress has been made in improving outcomes for most patients. Prevention and early detection are key to improving the prognosis of HNSCC. We have previously shown that persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in HNSCC, and that PI3K/mTOR inhibition exerts potent antitumor activity in a large series of genetically-defined and chemically-induced HNSCC models. However, potential immunosuppression and other dose-dependent side effects raise concerns regarding long term use of PI3K/mTOR inhibitors as chemopreventive agents. The repurposed drug metformin, used for frontline treatment of type 2 diabetes, decreases mTOR signaling in HPV- and HPV+ experimental HNSCC models and displays potent chemopreventive activity in mouse oral-premalignancy models. Furthermore, two recent large retrospective case-control cohort studies involving more than 300,000 diabetic patients demonstrated a decreased HNSCC risk in patients using metformin. Therefore, we conducted a single-arm, open label phase IIa clinical trial (NCT02581137) in individuals with oral premalignant lesions (OPL; oral leukoplakia or erythroplakia) to explore the potential of metformin for HNSCC prevention. Subjects were eligible if they had an OPL at any site with dysplasia or hyperplasia not associated with mechanical factors, and were otherwise healthy, without diabetes. They underwent pre- and post-treatment clinical exam of the oral cavity with lesion measurement and biopsy, along with saliva and blood collection. Eligible participants received metformin for 12 weeks (500 mg per day for the first week, 1,000 mg per day for the second week, and then 2,000 mg per day for the remaining treatment period). 26 participants were accrued and 22 were assessable for response. The toxicity profile was consistent with the known side effect profile of metformin. The clinical response rate was 18%, lower than the 30% spontaneous regression rate documented in several published long term oral leukoplakia trials. The clinical progression rate was also 18%. The significance of the clinical response assessment was limited by the short duration of treatment (only 12 weeks). Of interest, however, the histologic response rate was 59%, including 13% complete responses, and the histologic progression rate was 18%. Most of the responses consisted of a one grade improvement in histology. Circulating and tissue biomarker analyses, the latter focused on the impact of metformin on the AMPK-mTOR signaling network, are being analyzed. The goal of our studies is to provide a mechanistic framework for the selection of patients who may benefit from metformin for precision prevention of oral cancer. Citation Format: J Silvio Gutkind, Frank G. Ondrey, Denise Laronde, Miriam Rosin, Alfredo A. Molinolo, Charles Coffey, Beverly R. Wuertz, Leigha D. Rock, Huyen Huynh, H-H. Sherry Chow, Valerie D. Butler, Scott M. Lippman, Eva Szabo. M4OC-Prevent: Clinical evaluation of metformin for oral cancer precision prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4985.

Regular use of nonsteroidal anti-inflammatory drugs (NSAID) has been associated with reduced risk of breast cancer. Sulindac, a nonselective NSAID with both cyclooxygenase-2–dependent and –independent activities, is a candidate for breast chemoprevention. We conducted a phase Ib trial in 30 women at increased risk for breast cancer to evaluate the breast tissue distribution of sulindac at two dose levels (150 mg daily and 150 mg twice daily for 6 weeks), using nipple aspirate fluid (NAF) as a surrogate of breast tissue drug exposure. We also explored the effect of sulindac on drug-induced biomarkers in NAF. We show that sulindac and its metabolites partition to human breast as measured by NAF levels. Sulindac intervention did not decrease 13,14-dihydro-15-keto prostaglandin A2, a stable derivative of prostaglandin E2, in NAF, but exposure was associated with a significant trend towards higher levels of growth differentiation factor 15 in NAF in women receiving 150 mg twice daily (P = 0.038). These results are the first to show partitioning of sulindac and metabolites to human breast tissue and the first evidence for a potential dose-dependent effect of sulindac on growth differentiation factor 15 levels in NAF. Cancer Prev Res; 3(1); 101–7

Objectives: Cycloxygenase-2 (COX-2) is overexpressed in pancreatic tumors where it may be involved in inflammation, carcinogenesis, and the regulation of neoangiogenesis. The purpose of this trial was to evaluate the combination of intravenous gemcitabine with selective COX-2 inhibitor, celecoxib for effect on survival, disease progression, and tolerability in patients with advanced pancreatic cancer. In addition, limited pharmacokinetic and pharmacodynamic analyses were preformed. Materials and Methods: Eligible patients included those with locally advanced or metastatic pancreatic cancer with no prior chemotherapy and ECOG performance status 0-2. The treatment consisted of intravenous gemcitabine 1000 mg/m 2 weekly X 7 weeks and concurrent daily oral celecoxib 400 mg orally twice a day. Daily oral low-dose aspirin 81 mg was administered throughout the study as a precaution for increased risk of thrombotic events. Those with stable or responsive disease were continued on intravenous gemcitabine 1000 mg/m 2 weekly X 3 weeks and concurrent oral celecoxib. Results: Twenty five patients have been enrolled at 3 centers. Five patients had locally advanced cancer; 20 had metastatic disease. The most common grade 3/4 hematological toxicities were neutropenia (32%) and anemia (20%). Four patients (17%) had partial response and 7 (35%) demonstrated stable disease. The estimated 12-month survival rate was 15%, which did not reach the predetermined efficacy end point. There was a trend suggestive of correlation between a decrease in serum vascular endothelial growth factor and patient survival. Conclusion: The addition of celecoxib to gemcitabine therapy did not demonstrate significant improvement in measured clinical outcomes, in patients with advanced pancreatic cancer. Higher doses of celecoxib may be needed to observe significant antitumor activity.

Purpose: Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1α and vascular endothelial growth factor. Objectives of this study were to determine safety, tolerability, pharmacodynamics, and pharmacokinetics of PX-12, a small-molecule inhibitor of Trx-1. Experimental Design: Thirty-eight patients with advanced solid tumors received PX-12 at doses of 9 to 300 mg/m2, as a 1- or 3-h i.v. infusion on days 1 to 5, repeated every 3 weeks. Results: At the 300 mg/m2 dose level, one patient experienced a reversible episode of pneumonitis during the first cycle, and a second patient developed pneumonitis after the second cycle. Doses up to 226 mg/m2 were well tolerated, and grade 3/4 events were uncommon ( Conclusions: PX-12, the first Trx-1 inhibitor to enter clinical trials, was tolerated up to a dose of 226 mg/m2 by a 3-h infusion. Based on pharmacodynamic and pharmacokinetic data, a trial of prolonged infusion schedule of PX-12 has been initiated.

Aromatase inhibitors (AI) profoundly suppress estrogen levels in postmenopausal women and are effective in breast cancer prevention among high-risk postmenopausal women. Unfortunately, AI treatment is associated with undesirable side effects that limit patient acceptance for primary prevention of breast cancer. A double-blind, randomized trial was conducted to determine whether low and intermittent doses of letrozole can achieve effective estrogen suppression with a more favorable side-effect profile. Overall, 112 postmenopausal women at increased risk for breast cancer were randomized to receive letrozole at 2.5 mg once daily (QD, standard dose arm), 2.5 mg every Monday, Wednesday, and Friday (Q-MWF), 1.0 mg Q-MWF, or 0.25 mg Q-MWF for 24 weeks. Primary endpoint was suppression in serum estradiol levels at the end of letrozole intervention. Secondary endpoints included changes in serum estrone, testosterone, C-telopeptide (marker of bone resorption), lipid profile, and quality-of-life measures (QoL) following treatment. Significant estrogen suppression was observed in all dose arms with an average of 75% to 78% and 86% to 93% reduction in serum estradiol and estrone levels, respectively. There were no differences among dose arms with respect to changes in C-telopeptide levels, lipid profile, adverse events (AE), or QoL measures. We conclude that low and intermittent doses of letrozole are not inferior to standard dose in estrogen suppression and resulted in a similar side-effect profile compared with standard dose. Further studies are needed to determine the feasibility of selecting an effective AI dosing schedule with better tolerability. Cancer Prev Res; 9(2); 142–8. ©2015 AACR.

Purpose: Preclinical studies suggested that green tea or green tea catechins can modulate the activities of drug-metabolizing enzymes. We conducted this clinical study to determine the effect of repeated green tea catechin administration on human cytochrome P450 (CYP) enzyme activities. Methods: Forty-two healthy volunteers underwent a 4-week washout period by refraining from tea or tea-related products. At the end of the washout period, study participants received a cocktail of CYP metabolic probe drugs, including caffeine, dextromethorphan, losartan, and buspirone for assessing the activity of CYP1A2, CYP2D6, CYP2C9, and CYP3A4, respectively. Blood and urine samples before and 8 h after probe drug administration were collected to determine parent drug and metabolite concentrations for measurements of baseline CYP enzyme activities. Following the baseline evaluation, study participants underwent 4 weeks of green tea catechin intervention at a dose that contains 800 mg epigallocatechin gallate (EGCG) daily. The green tea catechin product was taken on an empty stomach to optimize the p.o. bioavailability of EGCG. The EGCG dose given in this study exceeded the amounts provided by average green tea consumption. Upon completion of the green tea catechin intervention, the postintervention CYP enzyme activities were evaluated as described above. Results: There are large between-subject variations in CYP enzyme activities in healthy individuals. Four weeks of green tea catechin intervention did not alter the phenotypic indices of CYP1A2, CYP12D6, and CYP12C9, but resulted in a 20% increase (P = 0.01) in the area under the plasma buspirone concentration-time profile, suggesting a small reduction in CYP3A4 activity. Conclusions: We conclude that repeated green tea catechin administration is not likely to result in clinically significant effects on the disposition of drugs metabolized by CYP enzymes. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2473–6)

Glutathione S-transferase (GST), a member of the phase II group of xenobiotic metabolizing enzymes, has been intensively studied at the levels of phenotype and genotype. The GST μ 1 (GSTM1) and GST θ 1 (GSTT1) genes have a null-allele variant in which the entire gene is absent. The null genotype for both enzymes has been associated with many different types of tumors. The aim of this study was to determine the possible differences in increased oxidative stress susceptibility to smoking within the GSTM1 and GSTT1 genotypes and the impact of high tea drinking on this. We designed a Phase II randomized, controlled, three-arm tea intervention trial to study the effect of high consumption (4 cups/day) of decaffeinated green or black tea, or water on oxidative DNA damage, as measured by urinary 8-hydroxydeoxyguanosine (8-OHdG), among heavy smokers over a 4-month period and to evaluate the roles of GSTM1 and GSTT1 genotypes as effect modifiers. A total of 133 heavy smokers (100 females and 33 males) completed the intervention. GSTM1 and GSTT1 genotype statuses were determined with a PCR-based approach. Multiple linear regression models were used to estimate the main effects and interaction effect of green and black tea consumption on creatinine-adjusted urinary 8-OHdG, with or without adjustment for potential confounders. Finally, we studied whether the effect of treatment varied by GSTM1 and GSTT1 status of the individual. Although there were no differences in urinary 8-OHdG between the groups at baseline, the between-group 8-OHdG levels at month 4 were statistically significant for GSTM1-positive smokers (P = 0.05) and GSTT1-positive smokers (P = 0.02). GSTM1-positive and GSTT1-positive smokers consuming green tea showed a decrease in urinary 8-OHdG levels after 4 months. Assessment of urinary 8-OHdG after adjustment for baseline measurements and other potential confounders revealed significant effect for green tea consumption (P = 0.001). The change from baseline was significant in both GSTM1-positive (t = −2.99; P = 0.006) and GSTT1-positive (P = 0.004) green tea groups, but not in the GSTM1-negative (P = 0.07) or GSTT1-negative (P = 0.909) green tea groups. Decaffeinated black tea consumption had no effect on urinary 8-OHdG levels among heavy smokers. Our data show that consumption of 4 cups of tea/day is a feasible and safe approach and is associated with a significant decrease in urinary 8-OHdG among green tea consumers after 4 months of consumption. This finding also suggests that green tea intervention may be effective in the subgroup of smokers who are GSTM1 and/or GSTT1 positive.

DNA is susceptible to damage by reactive oxygen species, and 8-hydroxydeoxyguanosine (8-OHdG) is probably one of the most abundant DNA lesions formed during oxidative stress. Several pathways exist for the removal or repair of this lesion from mammalian DNA. The most established is via the base excision repair enzyme, human 8-oxoguanine glycosylase (hOGG1). Several polymorphisms in the hOGG1 gene have been detected in human populations. We were interested in whether there were differences in increased oxidative stress susceptibility to smoking within the hOGG1 genotypes and the impact of high tea drinking on this. A phase IIb randomised, controlled, tea intervention trial was designed to study the effect of high consumption (four cups per day) of decaffeinated green or black tea on oxidative DNA damage, as measured by urinary 8-OHdG, among smokers over a 4-month period and to evaluate the role of the hOGG1 genotype as an effect modifier. A total of 120 smokers with hOGG1 data completed the 4-month intervention. The hOGG1 genotype status was determined with a polymerase chain reaction-based approach. Multiple linear regression models were used to estimate the main effects and interaction effect of green and black tea consumption on creatinine-adjusted urinary 8-OHdG, with or without adjustment for potential confounders. Finally, we studied whether the effect of treatment varied by hOGG1 status of the individual. Assessment of urinary 8-OHdG after adjustment for baseline measurements and other potential confounders revealed a highly significant decrease in urinary 8-OHdG after 4 months of drinking decaffeinated green tea (p = 0.001). No change in urinary 8-OHdG was seen among smokers assigned to the black tea group. We found the distribution of hOGG1 Ser326Cys genotypes among smokers to be 62%, 28% and 10% for Ser/Ser, Ser/Cys and Cys/Cys genotypes, respectively. Because the homozygous Cys/Cys genotype was present in only 10% of the study population, the mutant types (Ser/Cys and Cys/Cys) were combined and compared with the Ser/Ser genotype. We found no significant interaction between smoking, hOGG1 genotypes and tea intervention in terms of levels of urinary 8-OHdG. This finding suggests that green tea intervention might be effective in decreasing levels of urinary 8-OHdG among smokers regardless of their hOGG1 genotype.

Tea drinking has been associated with decreased occurrence of cancer and heart disease. One potential mechanism for these findings is the strong antioxidant effect of tea polyphenols. A phase II randomized controlled tea intervention trial was designed to study the effect of high consumption (4 cups/d) of decaffeinated green or black tea on oxidative DNA damage as measured by urinary 8-hydroxydeoxyguanosine (8-OHdG) among smokers over a 4-mo period. A total of 143 heavy smokers, aged 18-79 y, were randomized to drink either green or black tea or water. Levels of plasma and urinary catechins and urinary 8-OHdG were measured monthly. A total of 133 of 143 smokers completed the 4-mo intervention. Multiple linear regression models were used to estimate the main effects and interaction effect of green and black tea consumption on creatinine-adjusted urinary 8-OHdG, with or without adjustment for potential confounders. Plasma and urinary levels of catechins rose significantly in the green tea group compared with the other two groups. Assessment of urinary 8-OHdG after adjustment for baseline measurements and other potential confounders revealed a highly significant decrease in urinary 8-OHdG (-31%) after 4 mo of drinking decaffeinated green tea (P = 0.002). No change in urinary 8-OHdG was seen among smokers assigned to the black tea group. These data suggest that regular green tea drinking might protect smokers from oxidative damages and could reduce cancer risk or other diseases caused by free radicals associated with smoking.

Background/Purpose: Epidemiologic data implies that there are gender differences in lung cancer pathogenesis and possibly increased susceptibility to lung cancer in women. Chronic inflammation has been implicated as important modulator of human health by playing a significant role in both disease prevention and disease development. Several studies have demonstrated increased interleukin 6 (IL-6) and C-reactive protein (CRP) in the blood of smokers. The overall goal of this study was to develop a feasible tea intervention that will serve as a model for the chemoprevention of a wide range of tobacco-related diseases. Our immediate goal, that was addressed over a 4-year study period, was to determine the effects of high tea consumption on biological markers of chronic inflammation that mediate lung cancer risk, including, IL-6, CRP and antioxidant enzyme activities. Methods: We completed a 6-month randomized, controlled, double-blinded trial in a group of current and former smokers. Participants were stratified on smoking status and gender, and were randomized to green or black tea preparations or a control intervention (matching placebo). Levels of urinary iIL-6 and CRP are used to measure chronic inflammation and levels of superoxide dismutase (SOD) in red blood cells are used to measure antioxidant enzymes. Results: The study protocol was approved by all parties. A total of 138 participants (78 females and 60 males) completed the study. Our data show that il6 is significantly correlated with years of smoking and pack/year among smokers and former smokers. At the end of the 6-month intervention, female smokers in the green tea group showed a significant decrease in IL-6 (P=0.036) while male former smokers in the black tea group showed a significant decrease in CRP levels (P=0.012). There were no significant changes in dietary and serum antioxidant levels between the different groups. Conclusion: This data implies that smokers are more likely to benefit from green tea intake while the beneficial effects of black tea are observed among former smokers. Note: This abstract was not presented at the conference. Citation Format: Iman A. Hakim, Sami A. Aldaham, Janet Foote, H-H Sherry Chow. Modulating effects of green and black tea on biomarkers of chronic inflammation by gender and smoking status. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B14.

Laboratory studies suggest that vitamin D (VD) supplementation inhibits skin carcinogenesis. However, epidemiologic studies report mixed findings in the association between circulating VD levels and skin cancer risk. We conducted a clinical study to determine whether oral cholecalciferol supplementation would exert direct bioactivity in human skin through modulation of the VD receptor (VDR). We enrolled 25 individuals with serum 25-hydroxyvitamin-D levels

Individuals who consume cocaine illegally have long since adopted or explored the nasal route of administration. This study was designed to determine in an animal model whether nasally applied cocaine could be transported directly from the nasal cavity to the central nervous system. Male Sprague-Dawley rats were used in the study. The nasal cavity was isolated to prevent drainage of nasally applied dosing solution to nonnasal regions. Cocaine was then administered, either by intranasal (in) administration or by intravenous (iv) injection. At different times post dose, blood and tissues from different regions of the brain were collected. Cocaine concentrations in plasma and tissue samples were analyzed by HPLC. After iv administration, similar cocaine contents in different brain regions were observed. Following in administration, cocaine content in samples collected within 60 min post dose were found to differ considerably in different brain regions. The highest content was observed in the olfactory bulb, followed by the olfactory tract and then the remaining part of the brain. To allow comparison of brain cocaine content after iv and in administration, brain cocaine contents were normalized by plasma cocaine concentrations. The ratios of the area under the cocaine concentration-time curve (AUC) between the olfactory bulb and plasma at early times following in administration were significantly higher than those obtained after the iv dose (13.4 +/- 5.56 vs 6.16 +/- 0.94, p < 0.05, for AUC ratio up to 2 min post dose; 9.39 +/- 1.47 vs 7.34 +/- 0.59, p < 0.05, for AUC ratio up to 4 min post dose). At 1 min post dose, the olfactory bulb-to-plasma cocaine concentration ratios following in administration was three times those obtained after iv administration. After 1 min, the olfactory bulb-to-plasma concentration ratios following in administration were found to be similar to or smaller than those obtained after iv administration. The tissue-to-plasma concentration ratios in other brain regions following in administration were found to be smaller than those obtained following iv dosing. We conclude that nasally administered cocaine was transported directly from the nasal cavity to the brain but that only a very small fraction of the dose was transported via the direct pathway.

Background Nipple aspirate fluid (NAF) contains large amounts of protein thought to reflect the microenvironment of the breast, and is of interest in breast cancer prevention research. The correlation between specific NAF proteins to plasma concentrations have not been well studied in healthy women. We collected matched NAF and plasma from 43 healthy pre and postmenopausal women participating in an early phase clinical study to compare the levels of putative cancer protein biomarkers. We compared baseline NAF and plasma levels of epidermal growth factor (EGF), transforming growth factor-beta 1 (TGF-β1), and adiponectin and evaluated menopausal status and body mass index (BMI) as potential modifying factors. Findings NAF and plasma levels of EGF, TGF-β1 and adiponectin were not correlated. EGF and TGF-β1 levels in NAF of premenopausal women were significantly higher than postmenopausal women (P’s

Limonene is a bioactive food component found in citrus peel oil that has shown chemopreventive and chemotherapeutic activities in preclinical studies. We conducted an open-label pilot clinical study to determine the human breast tissue disposition of limonene and its associated bioactivity. We recruited 43 women with newly diagnosed operable breast cancer electing to undergo surgical excision to take 2 grams of limonene daily for two to six weeks before surgery. Blood and breast tissue were collected to determine drug/metabolite concentrations and limonene-induced changes in systemic and tissue biomarkers of breast cancer risk or carcinogenesis. Limonene was found to preferentially concentrate in the breast tissue, reaching high tissue concentration (mean = 41.3 μg/g tissue), whereas the major active circulating metabolite, perillic acid, did not concentrate in the breast tissue. Limonene intervention resulted in a 22% reduction in cyclin D1 expression (P = 0.002) in tumor tissue but minimal changes in tissue Ki67 and cleaved caspase-3 expression. No significant changes in serum leptin, adiponectin, TGF-β1, insulin-like growth factor binding protein-3 (IGFBP-3), and interleukin-6 (IL-6) levels were observed following limonene intervention. There was a small but statistically significant postintervention increase in insulin-like growth factor I (IGF-I) levels. We conclude that limonene distributed extensively to human breast tissue and reduced breast tumor cyclin D1 expression that may lead to cell-cycle arrest and reduced cell proliferation. Furthermore, placebo-controlled clinical trials and translational research are warranted to establish limonene's role for breast cancer prevention or treatment. Cancer Prev Res; 6(6); 577–84. ©2013 AACR.

Background: Several studies suggested that women may be more susceptible to oxidative damage induced by cigarette smoking, but the role of smoking status and antioxidant capacity in gender difference in susceptibility to oxidative damage has not been well studied. Methods: We conducted a cross-sectional analysis of the baseline data from 146 current and former heavy smokers enrolled in a chemoprevention trial to determine the gender difference in oxidative damage and antioxidant capacity. Oxidative DNA and lipid damage were assessed by urinary 8-hydroxy-2′-deoxyguanosine (8OHdG) and 8-isoprostaglandin F2α (8-iso-PGF2α), respectively. The erythrocyte antioxidant enzymes and serum fat-soluble antioxidants were measured to assess antioxidant capacity. Results: Female smokers had significantly greater levels of 8OHdG and 8-iso-PGF2α than males but the gender difference was only significant in current smokers. No gender difference was noted in erythrocyte antioxidant enzymes, although female current smokers had significantly lower or a trend for lower antioxidant enzymes. Female smokers had higher serum β-carotene than males. Biomarkers of oxidative damage did not correlate significantly with the antioxidant enzymes. Urinary 8OHdG did not correlate significantly with fat-soluble antioxidants. Inverse correlations were observed between urinary 8-iso-PGF2α and several serum carotenoids. Conclusion: Female current smokers have a greater extent of oxidative damage despite having higher serum levels of fat-soluble antioxidants. Lower erythrocyte antioxidant enzymes in female current smokers may contribute to the greater extent of oxidative damage. Impact: The study may help identify appropriate high-risk populations for interventions that attenuate oxidative damage and appropriate biomarkers for clinical studies in smokers. Cancer Epidemiol Biomarkers Prev; 21(12); 2193–200. ©2012 AACR.

Compelling preclinical and pilot clinical data support the role of green tea polyphenols in prostate cancer prevention. We conducted a randomized, double-blind, placebo-controlled trial of polyphenon E (enriched green tea polyphenol extract) in men with prostate cancer scheduled to undergo radical prostatectomy. The study aimed to determine the bioavailability of green tea polyphenols in prostate tissue and to measure its effects on systemic and tissue biomarkers of prostate cancer carcinogenesis. Participants received either polyphenon E (containing 800 mg epigallocatechin gallate) or placebo daily for 3 to 6 weeks before surgery. Following the intervention, green tea polyphenol levels in the prostatectomy tissue were low to undetectable. Polyphenon E intervention resulted in favorable but not statistically significant changes in serum prostate-specific antigen, serum insulin-like growth factor axis, and oxidative DNA damage in blood leukocytes. Tissue biomarkers of cell proliferation, apoptosis, and angiogenesis in the prostatectomy tissue did not differ between the treatment arms. The proportion of subjects who had a decrease in Gleason score between biopsy and surgical specimens was greater in those on polyphenon E but was not statistically significant. The study’s findings of low bioavailability and/or bioaccumulation of green tea polyphenols in prostate tissue and statistically insignificant changes in systemic and tissue biomarkers from 3 to 6 weeks of administration suggests that prostate cancer preventive activity of green tea polyphenols, if occurring, may be through indirect means and/or that the activity may need to be evaluated with longer intervention durations, repeated dosing, or in patients at earlier stages of the disease. Cancer Prev Res; 5(2); 290–8. � 2011 AACR.

Compelling preclinical and pilot clinical data support the role of green tea polyphenols in prostate cancer prevention. We conducted a randomized, double-blind, placebo-controlled trial of polyphenon E (enriched green tea polyphenol extract) in men with prostate cancer scheduled to undergo radical prostatectomy. The study aimed to determine the bioavailability of green tea polyphenols in prostate tissue and to measure its effects on systemic and tissue biomarkers of prostate cancer carcinogenesis. Participants received either polyphenon E (containing 800 mg epigallocatechin gallate) or placebo daily for 3 to 6 weeks before surgery. Following the intervention, green tea polyphenol levels in the prostatectomy tissue were low to undetectable. Polyphenon E intervention resulted in favorable but not statistically significant changes in serum prostate-specific antigen, serum insulin-like growth factor axis, and oxidative DNA damage in blood leukocytes. Tissue biomarkers of cell proliferation, apoptosis, and angiogenesis in the prostatectomy tissue did not differ between the treatment arms. The proportion of subjects who had a decrease in Gleason score between biopsy and surgical specimens was greater in those on polyphenon E but was not statistically significant. The study's findings of low bioavailability and/or bioaccumulation of green tea polyphenols in prostate tissue and statistically insignificant changes in systemic and tissue biomarkers from 3 to 6 weeks of administration suggests that prostate cancer preventive activity of green tea polyphenols, if occurring, may be through indirect means and/or that the activity may need to be evaluated with longer intervention durations, repeated dosing, or in patients at earlier stages of the disease. Cancer Prev Res; 5(2); 290–8. ©2011 AACR.

Resveratrol has been shown to exhibit cancer-preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacologic doses of resveratrol on drug- and carcinogen-metabolizing enzymes. Forty-two healthy volunteers underwent baseline assessment of cytochrome P450 (CYP) and phase II detoxification enzymes. CYP1A2, CYP2D6, CYP2C9, and CYP3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. Blood lymphocyte glutathione S-transferase (GST) activity and GST-π level and serum total and direct bilirubin, a surrogate for UDP-glucuronosyl transferase (UGT) 1A1 activity, were measured to assess phase II enzymes. After the baseline evaluation, study participants took 1 g of resveratrol once daily for 4 weeks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-π level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacologic doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions. Cancer Prev Res; 3(9); 1168–75. ©2010 AACR.

Purpose Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. Patients and Methods Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. Results There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve–dependent decrease in cystine levels 8 hours after dosing at ≥ 750 mg/m2/d. Conclusion The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.

Experimental studies suggest that vitamin D (VD) plays an important role in skin carcinogenesis. In humans, epidemiologic studies have reported mixed findings in the association between circulating vitamin D levels and skin cancer risk. We conducted a pilot clinical study to determine whether oral VD supplementation would exert any bioactivity in human skin. Methods: The study accrued twenty-five healthy individuals with serum 25-hydroxyvitamin D levels Citation Format: Clara Curiel-Lewandrowski, Jean Tang, Janine Einspahr, Yira Bermudez, Chiu-Hsieh Hsu, Melika Rezaee, Alex Lee, Joe Tangrea, Howard Parnes, David Alberts, H-H. Sherry Chow. Pilot study on the bioactivity of vitamin D in the skin after oral supplementation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3248. doi:10.1158/1538-7445.AM2014-3248

In vitro data and pilot clinical trial data suggest that green tea catechins may possess chemopreventive activity for cervical cancer and its precursor lesions. We conducted a randomized, double-blind, placebo controlled trial of Polyphenon E (decaffeinated and enriched green tea catechin extract) in women with persistent human papillomavirus (HPV) infection and low grade cervical intraepithelial neoplasia (CIN1) to evaluate the potentials of Polyphenon E for cervical cancer prevention. Ninety-eight eligible women were randomized to receive either Polyphenon E (containing 800 mg epigallocatechin gallate) or placebo once daily for 4 months. The primary study outcome was oncogenic HPV clearance and clearance of CIN1. Polyphenon E was shown to be acceptable, safe and well tolerated. There was no difference in the response rate by treatment allocation. Complete response, defined as negative for high risk HPV and normal histopathology, was noted in 7 (17.1%) and 6 (14.6%) women in the Polyphenon E and placebo arms, respectively. Partial response, defined as clearance of oncogenic HPV with evidence of CIN1, occurred more frequently in the placebo group 6 (14.6%) vs. 1 (2.4%) in the Polyphenon E arm. Progression, defined as persistent oncogenic HPV with histopathologic evidence of progression, was more common in the Polyphenon E group [3 (7.7%) vs. 6 (14.6%) in the placebo arm, although neither of these observations were statistically significant. Based on the largest randomized placebo-controlled trial of a green tea extract for HPV related cervical disease, we conclude that four months of Polyphenon E intervention did not promote the clearance of persistent high risk HPV and related CIN 1. Further studies may be necessary to better delineate the risk factors for persistent HPV infection and biology of the disease to facilitate the evaluation of chemopreventive strategies. Citation Format: Tomas Nuno, Francisco A.R. Garcia, Terri Cornelison, Amy L. Mitchell, David L. Greenspan, John W. Byron, Chiu-Hsieh Hsu, David S. Alberts, Sherry Chow. Results of a phase II randomized, double-blind, placebo controlled trial of Polyphenon E in women with persistent high-risk HPV infection and low-grade cervical intraepithelial neoplasia. [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 C50.

Resveratrol, a phytochemical produced by a restricted number of plant species in response to stress, has exerted compelling breast cancer preventive activities in preclinical studies. Resveratrol not only acted as an estrogen receptor agonist/antagonist and inhibited aromatase but also affected multiple carcinogenesis pathways and multiple targets within a pathway. Resveratrol also demonstrated beneficial effects on metabolic disturbances in rodent models for obesity. We conducted an open label, single arm pilot study of resveratrol in postmenopausal women with high body mass index (BMI ≥ 25 kg/m2), a risk factor for breast cancer. The primary objective was to determine the effect of resveratrol on serum estradiol levels with secondary endpoints being measurement of modulation of multiple systemic markers associated with breast cancer risk. Forty eligible subjects were recruited to initiate the resveratrol intervention (1 gm resveratrol daily for 12 weeks) with six withdrawn early due to adverse events. Thirty-four subjects completed 12 weeks of resveratrol intervention. We found that resveratrol intervention did not result in significant changes in serum concentrations of estradiol, estrone, and testosterone in the study cohort but significantly increased serum levels of sex steroid hormone binding globulin (10% increase from baseline, p < 0.01). Resveratrol intervention resulted in a significant increase in urinary 2-hydroxyestrone (2-OHE1) levels (73% increase from baseline, p < 0.01) leading to a favorable change in urinary 2-OHE1/16α-OHE1 ratio (85% increase from baseline, p < 0.01). Serum leptin levels were suppressed significantly (10% decrease from baseline, p < 0.01) following resveratrol intervention whereas serum adiponectin levels were not changed. The most common possibly or probably related adverse events were diarrhea, constipation, and abdominal discomfort. One participant had a possibly related serious grade 4 elevation in hepatic ALT and AST enzymes at the post-intervention visit which resolved after less than 3 months of follow-up. Aside from this event, resveratrol intervention did not result in clinically significant changes in hematology and blood chemistry. We conclude that daily 1 gm dose of resveratrol did not affect the levels of circulating sex steroid hormones in postmenopausal women with high BMI but resulted in favorable changes in serum sex steroid binding globulin and leptin levels and urinary 2-OHE1/16α-OHE1 ratio that may be associated with reduced breast cancer risk. However, the observed adverse effects advocate for the consideration of lower doses for further clinical development of resveratrol for cancer prevention. (supported by a contract, N01-CN-35158, from the National Cancer Institute, Division of Cancer Prevention) Citation Format: H-H. Sherry Chow, Linda L. Garland, Brandy M. Heckman-Stoddard, Chiu-Hsieh Hsu, Valerie D. Butler, Catherine A. Cordova, Wade M. Chew, Terri L. Cornelison. Modulating effects of resveratrol on systemic markers associated with breast cancer risk: a pilot clinical study in postmenopausal women with high adiposity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 159. doi:10.1158/1538-7445.AM2013-159

Background. Limonene is a bioactive food component found in citrus peel oil that has demonstrated chemopreventive and chemotherapeutic activities in preclinical studies. To better characterize its mechanism of action in the clinical setting, we measured the serum metabolomic profiles of breast cancer patients before and after receiving a short-term limonene intervention. Methods. Forty women with stage 0 - II breast cancer received 2 g QD limonene daily for 2 - 6 weeks (21.5 ± 8.8 days) before surgical resection of their tumor. Pre/post intervention blood draws were taken to assess serum metabolomic profiles. Metabolomic analysis was performed on the gas chromatography mass spectrometry and liquid chromatography mass spectrometry platforms established at Metabolon, Inc. Results. Of the 397 identified biochemicals, 71 changed significantly (p0.4) in an exploratory analysis. Conclusions. This global metabolomic profiling study revealed several novel mechanistic insights into the potential clinical activities of limonene. Efforts are ongoing to correlate these metabolic changes to carcinogenesis, clinical characteristics, and risk markers measured in breast tissue and serum. Citation Format: Jessica A. Miller, Kirk Pappan, Chengcheng Hu, Elizabeth J. Want, Hector Keun, Julie E. Lang, H-H Sherry Chow. Modulation of the serum metabolomic profiles of breast cancer patients after receiving limonene intervention. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 160. doi:10.1158/1538-7445.AM2013-160

Background: Limonene is a highly lipophilic monoterpene found in citrus peel oil that has demonstrated anticancer properties in preclinical studies. The purpose of this study was to evaluate whether limonene and its primary metabolite perillic acid (PA) would distribute extensively to the breast tissue and reach an effective drug concentration. Secondary endpoints included evaluation of changes in cancer-related biomarkers in plasma and tissue. Methods: Participants (N = 40) with newly diagnosed stage 0 - 2 breast cancer took 2 grams daily of oral limonene for 2 - 6 weeks (21.5 ± 8.8 days) prior to planned surgical tumor resection. Blood was drawn pre/post intervention for measurement of serum concentration of limonene, PA, and protein biomarkers, as well as to assess toxicity profiles. A small piece of breast tissue adjacent to the tumor mass was also collected for analysis of limonene and PA levels. Limonene and PA levels in tissue and serum were analyzed using specific chromatography-based assays. Results: Limonene was found to preferentially concentrate in breast tissue (332.3 + 336.1 uM) versus plasma (0.49 + 0.67 uM) with tissue-to-plasma concentration ratio (TPCR) of 1,667 + 312.5 (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3558. doi:1538-7445.AM2012-3558

Some epidemiological studies and several experimental publications suggest that regular use of NSAIDs may reduce the risk of melanoma. Proposed mechanisms of action include: inhibition of MAP kinase activity and nuclear translocation, reduction in the concentration of prostaglandins associated with the inhibition of VEGF and bFGF production and HIF-1α stabilization, reduction of the activation state of the VEGF and Ftl-1 genes, and inhibition of PI-3 kinase/Akt signaling pathway. However, specific information on the ability of NSAIDs to reach melanocytes in vivo and to modulate key biomarkers in pre-neoplastic lesions, such as dysplastic nevi, have not been evaluated to date. Methods: A phase IIa placebo controlled clinical intervention trial was designed with the primary end point to determine whether oral sulindac and related metabolites were present in benign nevi (BN) after an 8 week course of oral sulindac; secondary end points were included to determine whether a short exposure to sulindac had an effect on apoptosis and VEGF expression in atypical nevi (AN), as well as measurement of sulindac and metabolite levels in plasma. Exploratory objectives will evaluate the feasibility of reverse phase protein microarray to identify intervention related changes in cell signaling proteins, focusing initially on the pAKT/mTOR pathway and COX expression. Fifty healthy subjects with ≥ 4 large (≥5 mm and < 15 mm) AN and one BN were enrolled between 2/09 and 7/10. Subjects underwent clinical and dermoscopic evaluation of their melanocytic lesions with 2 AN randomized to be excised at baseline for biomarker evaluation and 2 AN to post-intervention evaluation. Subsequently, participants were randomized to receive sulindac (150 mg BID) or placebo for 8 weeks. Upon completion of the intervention the residual 2 AN and the BN were surgically removed. Results: To date, accrual has been completed and study intervention in all subjects is expected to be concluded in 09/10. The study intervention was well tolerated with some mild or moderate gastrointestinal adverse events that are possibly or probably related to the intervention. Sulindac, sulindac sulfide, sulindac sulfone concentrations were 0 — 1.4, 0 −9.07, and 0 — 6.1 µg/ml, respectively, in 41 post-intervention plasma samples analyzed to date. Sulindac, sulindac sulfide, sulindac sulfone concentrations were 0 — 5.2, 0 — 0.25, and 0 — 14.27 µg/g, respectively, in 40 postintervention BN samples. Conclusion: Current results suggest that NSAIDs, in particular sulindac and the active sulindac metabolites, can reach measurable levels in the skin, and specifically in melanocytic nevi, further supporting the need to assess the effect of this group of drugs as chemopreventive agents for melanoma. Supported by N01CN35158 from the National Cancer Institute, Division of Cancer Prevention. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A66.