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Supplemental Methods and Materials. ACF Phospho-ERK and ERK Level Quantification.

Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use. Cancer Prev Res; 8(3); 222–30. ©2015 AACR.

Perspective on this Article from Risk of Cardiovascular Events in a Randomized Placebo-Controlled, Double-Blind Trial of Difluoromethylornithine plus Sulindac for the Prevention of Sporadic Colorectal Adenomas

On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed. Cancer Prev Res; 7(5); 496–504. ©2014 AACR.

PDF file - 3911KB, Supplementary Figure S1. Examples of classifications of nevomelanocytic neoplasms histopathologically evaluated for the primary endpoint of the study. Supplementary Figure S2. Examples of a target atypical nevus photographed pre and post treatment. Supplementary Figure S3. Examples of back photos pre and post treatment. Supplementary Figure S4. CONSORT Flowchart for all study subjects. Supplementary Figure S5. Bland-Altman plot of histopathologic regression of atypical nevi. Supplementary Figure S6. Assessment of clinical regression of atypia. Supplementary Figure S7. Bland-Altman plots of (A) HIF-1 percent of nuclear staining, (B) e-Cadherin percent of cytoplasmic staining, (C) N-Cadherin percent of cytoplasmic staining and (D) VEGF percent of cytoplasmic staining. Supplementary Figure S8. Bland-Altman plots of (A) RelA percent of cytoplasmic staining, (B) p21 percent of nuclear staining, and (C) ki-67 percent of nuclear staining.

Supplemental Figure 1. Metformin effects on insulin, AMPK, mTOR

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In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum α-fetoprotein (AFP) level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 g/d, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. One hundred ten subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury or markers of oxidative stress or antioxidant potential. Cancer Prev Res; 8(9); 864–72. ©2015 AACR.

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Perspective on this Article from Longitudinal Assessment of Air Conduction Audiograms in a Phase III Clinical Trial of Difluoromethylornithine and Sulindac for Prevention of Sporadic Colorectal Adenomas

Supplemental Table 1: Change from Week 0 to Week 24 for routine blood tests of liver function or injury. Supplemental Table 2: Compliance with study medicine among 87 subjects who completed the study. Supplemental Table 3: Change from Week 0 to Week 24 in quality of life as assessed with SF-36 and CLDQ.

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Supplemental Figure 1a: SF-36. SF-36 mental component score among subjects randomized to SAMe or placebo, at baseline, Week 12 and Week 24. Supplemental Figure 1b: SF-36 physical component score among subjects randomized to SAMe or placebo, at baseline, Week 12 and Week 24. Only subjects with SF-36 at all three time points were included in the analysis. Supplemental Figure 2: CLDQ. Chronic liver disease questionnaire among subjects randomized to SAMe or placebo, at baseline, Week 12 and Week 24. Only subjects with CLDQ at all three time points were included in the analysis.

PDF file - 64KB, Supplementary Table S1. Descriptive statistics for concordance evaluation of positive control slides. Supplementary Table S2. Evaluation of laboratory data.

Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 (P = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.

Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use. Cancer Prev Res; 8(3); 222–30. ©2015 AACR.

On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed. Cancer Prev Res; 7(5); 496–504. ©2014 AACR.

Nonsteroidal anti-inflammatory drugs (NSAID) have been associated with adverse cardiovascular (CV) outcomes in cancer prevention and other clinical trials. A recent meta-analysis suggested that baseline CV risk is associated with NSAID-associated adverse CV events. We evaluated the effect of baseline CV risk on adverse CV events in a phase III trial of difluoromethylornithine (DFMO) plus the NSAID sulindac versus placebo in preventing colorectal adenomas. Trial data were analyzed to determine baseline CV risk. CV toxicity outcomes were then assessed overall and excluding high CV-risk patients. Baseline CV risk scores were evenly distributed within our overall trial population of 184 placebo (low risk, 27%; moderate risk, 34%; high risk, 39%) and 191 DFMO/sulindac (low risk, 30%; moderate risk, 29%; high risk, 41%) patients. In patients with a high baseline CV risk, the number of adverse CV events was greater among DFMO/sulindac (n = 9) than among placebo (n = 3) patients. Excluding patients with a high baseline CV risk, the numbers of adverse CV events were similar in the DFMO/sulindac (n = 7) and placebo (n = 6) arms. A high CV risk score at baseline may confer an increased risk of CV events associated with treatment with DFMO/sulindac, and a low baseline score may not increase this risk. These results have implications for future NSAID-based cancer prevention clinical trials.

Purpose: We have proposed to characterize the mechanism through which bioactive surgical sutures generate a TH1 immune response and to define the immune-stimulating half-life of the sutures.Experimental Design: Bioactive sutures of interferon γ (IFNγ), interleukin 2 (IL-2), anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNγ sutures were used to stimulate lymphocytes from normal donors and from head and neck cancer patients in vitro over a 24-day period. Cell supernatants were analyzed by ELISA, and T cells were phenotyped to characterize the immune response generated. Intracellular cytokine staining was performed to measure the expansion of flu-specific T cells. Electromobility shift assay and supershift assay were used to measure the intranuclear DNA binding activity of nuclear factor κB and its p65 subunit in T cells activated by sutures in the presence and absence of a proteasome inhibitor, MG-132.Results: Anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNγ generated a prolonged TH1 immune response for 18 days in vitro. Anti-CD3/CD28 expanded flu-specific T cells. Activated T cells demonstrated enhanced CD40 ligand (CD40L) expression within 72 hours of stimulation, which stimulated other cells to secrete IL-12. Stimulated T cells demonstrated increased intranuclear expression of nuclear factor-κB, which was blocked by MG-132, and also reduced CD40L and IL-12 expression.Conclusions: This is the first report to demonstrate that bioactive surgical sutures can generate a prolonged TH1 immune response and expand flu-specific T cells. Bioactive sutures, which are primarily a T-cell stimulant, also stimulated other cells to secrete IL-12 and prolonged the immune response. Sutures may provide a novel in situ stimulating strategy for enhancing the immune system of cancer patients.

Background: Despite advances in colorectal cancer (CRC) screening, early detection, and treatment, CRC remains the 2nd most common cancer cause of death in the U.S.. Obesity is increasing in incidence in the U.S., and has been implicated in colorectal adenoma (CRA) risk, risk of CRA recurrence, and risk of CRC. Obese patients with history of CRA are a high-risk group that may benefit from novel CRC prevention strategies. There is early evidence for reduced cancer mortality among metformin users. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice, as evidenced by metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPk, decreased ratio of pmTOR/mTOR, and decreased ratio of pS6Ser235/S6Ser235 in polyp specimens. We hypothesized that metformin would affect colorectal tissue S6Ser235 similarly in humans, targeting obese patients with recent history of CRAs as a high-risk group. Methods: A phase IIa clinical biomarker trial was conducted across 3 clinical sites via the NCI-funded Southern California Chemoprevention Program. Eligible participants included non-diabetic, obese patients (BMI >30) with history of colorectal adenoma within the past 3 years, age ≥ 35 years and ≤ 80 years. All patients received an upward titration of metformin over 3 weeks to 1000mg po bid, which was continued until the end-of-study (EOS) at 12 weeks. Rectal mucosa biopsies were obtained at baseline (BL) and at time of EOS endoscopy. Tissue S6Ser235 immunostaining was analyzed in a blinded fashion by the study pathologist using Histo Score (HScore) analysis. A paired t-test was used to examine the effect of metformin on activated S6serine235 (i.e., the ratio of pS6serine235/ S6serine235). Results: 45 patients were consented to achieve 32 eligible subjects. 4 subjects were removed from study due to Adverse Events (1 SAE, unrelated). In order of frequency, the most common AEs were diarrhea, cramping, flatulence, nausea, stomach pain; 80% of participants had Grade 1 AE, 27% had grade 2 AE. Mean (SD) weight and body mass index at BL were 105.2 (17.42) kg and 34.9 (5.57) respectively. Weight did not significantly differ over the course of the study. Glucose levels at EOS did not significantly differ from BL. Vitamin B12 levels were significantly reduced at EOS vs. BL (-46.7 pg/mL, 95% CI -73.2 to -20.2). Comparing EOS to BL tissue S6Ser235 by IHC HScore analysis, no significant differences were observed. Mean (SD) Hscore at BL was 1.1 (0.57) and 1.1 (0.51) at EOS. Median HScore change was 0.032 (p=0.77). Conclusions: Among obese CRA patients, 12 weeks of oral metformin 1000mg twice daily does not reduce pS6 levels in the rectal mucosa. Other potential mechanisms of action have not yet been analyzed. Data from this clinical trial indicate that metformin can be used safely in a non-diabetic population. Further research is needed to determine what effects, if any, metformin has on the target tissue of origin (colorectum) relevant to colorectal carcinogenesis if metformin is to be pursued as a CRC chemopreventive agent. Citation Format: Jason A. Zell, Christine E. McLaren, Timothy R. Morgan, Michael J. Lawson, Sherif Rezk, Gregory C. Albers, Wen-Pin Chen, Joseph C. Carmichael, Luz Rodriguez, Eva Szabo, Leslie Ford, Michael Pollak, Frank L. Meyskens. A Phase IIa trial of metformin for colorectal cancer risk reduction among patients with a history of colorectal adenomas and elevated body mass index. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A21.

Background: The goal of this multi-site prospective study is to validate a safe, painless imaging method to measure the change in breast density caused by hormonal chemotherapy treatments such as tamoxifen. Recent studies have demonstrated that hormonal therapies are more effective at reducing risk in women who exhibit >10% reduction in breast density compared to women who had little or no density change, suggesting that breast density is a predictor of tamoxifen effectiveness. Current methods to measure breast density include MRI and mammography, however frequent applications of these modalities are limited due to cost and x-ray exposure, respectively. Alternatively, we are testing an imaging method that uses safe near-infrared light to measure breast tissue physiology called diffuse optical spectroscopic imaging (DOSI). Trial Design and Eligibility: The primary aim of the study is to determine whether the percentage change in the DOSI measurement of water correlates with the change in the MRI measurement of breast density after 18 months of treatment in the contralateral normal breast of breast cancer patients receiving tamoxifen. Other DOSI-derived parameters such as lipid content and hemoglobin concentration will be examined in secondary aims. Two groups of women are being recruited for the study: Pre-menopausal subjects receiving tamoxifen (treatment group) and pre-menopausal subjects not receiving chemoprevention agents (control group). Participants are measured with DOSI and non-contrast MRI before, and 6, 12 and 18 months after beginning tamoxifen. Eligible subjects are pre- and peri-menopausal females older than 21 years of age who have not and do not intend to receive chemotherapy, radiation, or surgical cancer treatment to the imaged breast, and are not pregnant or nursing. Study sites include the University of California, Irvine and San Francisco campuses. Statistical Methods: At a 5% significance level, the pre-determined power of the study is sufficient to detect the difference between the treatment and control groups by measuring the percentage change of breast tissue water concentration with DOSI. The research hypothesis is that the mean difference from baseline for tissue water concentration from DOSI will be greater for the tamoxifen-treated group than the control group. For water concentration and for MRI breast density, a two-sided independent sample t-test will be used to test the null hypothesis that the mean difference from baseline is the same for the tamoxifen-treated and control groups. As a secondary analysis, a multivariate mixed effects model will be built using the observed DOSI parameter or MRI breast density measured from each patient as the outcome variable, and predictor variables to include treatment group and measurement time, in addition to relevant clinical and demographic variables. Accrual Update: Out of the target accrual of 36, 11 subjects (6 treatment and 5 control group) have been enrolled to date. Enrollment is open until 11/30/2015. Citation Format: Thomas D OSullivan, Anais Leproux, Alice M Police, Dorota Wisner, Christine McLaren, Wen-Pin Chen, Albert E Cerussi, Min-Ying Su, Bruce J Tromberg. Predicting hormonal therapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Ongoing clinical study [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 OT3-2-07.

Colorectal cancer (CRC) progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal Growth Factor Receptor (EGFR) inhibitors can shrink advanced tumors including CRC. There is significant evidence that EGFR also plays important roles in CRC initiation, and that EGFR inhibitors block tumorigenesis. We therefore performed a double-blind randomized trial (N=45) to test whether the EGFR inhibitor erlotinib (25mg, 50mg and 100mg doses) given for up to 28 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to CRC, and normal rectal tissue. Participants were stratified by NSAID dose. Erlotinib was well tolerated and there were no unanticipated adverse events. Colorectal ACF and normal tissue EGFR signaling changes with erlotinib were modest and there was no clear dose response. However, individuals with high baseline EGFR signaling may potentially constitute a subset that could benefit from this strategy. Overall, our results support the safety of erlotinib in the chemoprevention setting, but efficacy in colorectal EGFR signaling inhibition is likely insufficient to merit further studies without additional pre-screening stratification. Citation Format: Steven Lipkin, Asmita Bhattacharya, Timothy Morgan, Jason Zell, Daniel Gillen, Vanessa Wong, Jinah Chung, Wen Pin Chen, Rachel Gonzalez, Frank Meyskens, Luz Rodriguez, Eva Szabo, Robert Carroll, Richard Benya. A phase IIa randomized, double-blind trial of erlotinib in inhibiting EGF receptor signaling in aberrant crypt foci of the colon. [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 CN07-01.

Difluoromethyl ornithine (DFMO), an ornithine decarboxylase inhibitor, and sulindac reduced the occurrence of colorectal adenomas by 70% in a phase III randomized placebo controlled clinical trial. The goal of the current study was to compare adenoma location in the colorectum and biomarker expression by immunohistochemistry of formalin fixed paraffin embedded adenomas from treatment and placebo groups in the trial. To take into account the relationship between the locations in the colorectum of multiple adenoma that were removed from individual subjects, the generalized estimation equation (GEE) method was applied for all analyses. The decrease in the reappearance of metachronous adenomas was similar throughout the colorectum in subjects treated with DFMO and sulindac (P = 0.44). For TP53, Ki67, and c-MYC there were no significant differences in the estimated mean percent of cells staining positive between treated and untreated subjects (P>0.5 for all). For BCL-2, LC3B, CEA, sialy1-Tn, cleaved caspase 3 and apoptosis, the proportion of adenoma with expression levels 1+ to 3+ did not differ between subjects treated with DFMO plus sulindac versus those treated with double placebos. For hMSH2, hMSH6, hMLH1 and hPMS2, there was a loss of staining of a greater number of cells on average in adenomas from the control group compared to adenomas from the subjects treated with DFMO and sulindac. For hMSH2, this difference was statistically significant (P = 0.0004). This finding raises the possibility that DFMO and sulindac protect adenomas from loss of DNA mismatch repair protein expression and provides a rationale for further study of the possible role of DFMO and sulindac on DNA mismatch repair protein regulation and chemoprevention in patients at risk for colorectal carcinoma. In conclusion, DFMO decreases the occurrences of adenomas throughout the colorectum, including the right colon, and may have an effect on DNA mismatch repair enzyme expression. These findings provide further rationale for the use of DFMO as a chemopreventative agent for colorectal carcinoma. Citation Information: Cancer Prev Res 2011;4(10 Suppl):PR-01.

Background: The pharmacologic targeting of polyamines and prostaglandin E2 (PGE2) has proven efficacy for colorectal adenoma prevention. However, the contribution of these analytes as biomarkers of drug response has not been investigated. Methods: We analyzed the relationships between rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment, and risk of adenoma within the context of a phase IIb/III trial of combination difluoromethylornithine (DFMO) plus sulindac for the prevention of colorectal adenoma. Results: We detected no differences in the change in PGE2 levels between the two groups for any time points, but we show a statistically significant decrease in spermidine:spermine levels and in putrescine levels in the DFMO/sulindac group at 12 and 36 months compared to the placebo arm. When we asked whether or not change in polyamine or putrescine levels was associated with adenoma recurrence in the treatment arm only, we found no difference in the rate of metachronous events by change in polyamine or PGE2 levels in the treatment arm. We also found no evidence that polyamine or PGE2 levels were associated with risk of adenoma when we restricted the analysis to the placebo arm only. Of interest, we found that participants with low baseline spermidine:spermine levels who received DFMO/sulindac achieved a significantly greater benefit from treatment (RR = 0.15, 95% CI = 0.06 to 0.40) than those with high baseline spermidine:spermine receiving drug (RR = 0.50, 95% CI = 0.27 to 0.92). Conclusions: DFMO/sulindac significantly suppressed the production of rectal mucosal polyamines, but the magnitude of change was not predictive of response to intervention. This was likely due to the large effect of DFMO/sulindac on adenoma recurrence. We found no evidence in the placebo arm that baseline polyamine or PGE2 were associated with the risk of developing adenoma. The modulating effect of baseline spermidine:spermine levels on metachronous adenoma, in those individuals receiving the drug combination, provides evidence of differential agent-effectiveness by steady-state polyamine levels that should be investigated in future studies. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A29.