Limburg, Paul J.

Abstract Background: Different molecules within coffee may be pro-carcinogenic, while others may have anti-oxidant and anti-neoplastic effects. Hence, it can be hypothesized that coffee may have differing risk associations with specific colorectal cancer (CRC) subtypes. The aim of this study was to evaluate associations between coffee consumption and incident CRC overall, by anatomic subsite, and by molecularly defined tumor subtypes, in the population-based Iowa Women's Health Study (IWHS). Methods: IWHS participants, ages 55-69 years, provided dietary intake estimates using self-reported food frequency questionnaires at baseline (1986). From 35,216 women included the final analysis, 1298 developed CRC (673 with proximal CRC, 597 with distal CRC) through December 31, 2002 (end of the IWHS molecular epidemiology project study period). Archived, paraffin-embedded tissue specimens for 732 representative CRC cases were collected and analyzed to determine if coffee consumption (none or <1 cup/month, <1 cup/week, 1 cup/day, 2-3 cups/day and ≥4 cups/day) was associated with microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation status (BRAF-wildtype or BRAF-mutated), KRAS mutation status (KRAS-wildtype and KRAS-mutated), p53 protein expression level (p53 absent, low or high) and estrogen receptor β protein expression level (ERβ absent, low or high). Multivariable Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) with adjustment for age, smoking, alcohol use, diabetes, body mass index and waist-hip ratio, physical activity, estrogen use, dietary intake of fat, calcium, vitamin E, sucrose, red meat and methionine. P-values were not adjusted for multiple testing. Results: There was no significant difference in the risk of overall (RR, 1.05; 95% CI, 0.85-1.29; Ptrend=0.50), proximal (RR, 0.91; 95% CI, 0.68-1.21; Ptrend=0.57) or distal CRC (RR, 1.18; 95% CI, 0.86-1.64; Ptrend=0.19) in women who consumed ≥4 cups of coffee/day (caffeinated or decaffeinated), as compared to non-consumers. By CRC molecular subtypes for these same two exposure groups, women with ≥4 cups of coffee/day were more likely to develop ERβ-low CRC (RR, 2.98; 95% CI, 1.04-8.51; Ptrend=0.06), though no significant associations were observed for caffeinated or decaffeinated coffee specifically. In contrast, women who consumed ≥4 cups of decaffeinated coffee/day were less likely to develop MSI-L/MSS (RR, 0.57; 95% CI, 0.36-0.92; Ptrend=0.04) and BRAF-WT (RR, 0.69; 95% CI, 0.44-1.06; Ptrend=0.06) CRCs than non-consumers. Women who consumed ≥4 cups of caffeinated coffee/day were also less likely to develop p53-low CRCs (RR, 0.53; 95% CI, 0.24-1.15; Ptrend=0.02). Null associations were observed between decaffeinated coffee consumption and risk of CIMP-, KRAS- and p53- defined CRC subtypes, as well as between caffeinated coffee consumption and risk of MSI-, BRAF-, CIMP- or KRAS-defined CRC subtypes. Conclusion: In this prospective cohort study of older women, though coffee consumption was not associated with risk of overall or site-specific CRC, unique associations were observed with molecularly defined CRC subtypes, supporting a need for further investigation of the potential pro- and anti-carcinogenic effects of coffee constituents on biologic targets involved in colorectal carcinogenesis. Citation Format: Siddharth Singh, Robert Vierkant, Lori Tillmans, Alice Wang, Daniel Weisenberger, Peter Laird, Maki Inoue-Choi, Andrea Mariani, Charles Lynch, Kristin Anderson, Amy French, Robert Haile, Lisa Harnack, John Potter, Susan Slager, Thomas Smyrk, Stephen Thibodeau, James Cerhan, Paul Limburg. Coffee consumption and colorectal cancer risk by molecularly defined subtypes in a prospective cohort study of older women. [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 A44.

OBJECTIVES: Expression of prostaglandin biosynthetic pathway enzymes in mucinous pancreatic cysts is unknown. Cyclooxygenase-2 (COX-2) inhibition is a potential cancer chemoprevention strategy for these lesions. We evaluated the expression of COX-2, cytosolic phospholipase A2 (cPLA2), and protein kinase B (AKT) in the epithelium of pancreatic cysts and correlated enzyme expression with aspirin (ASA) use and cyst fluid prostaglandin E 2 (PGE 2 ) concentration. METHODS: Pathology of 80 resected pancreatic cysts was reviewed. Expression of COX-2, cPLA2, and AKT was quantified by tissue immunohistochemistry immunoreactivity scores (IRSs). IRS values were compared between cyst types and (in 30 cases) with matched cyst fluid PGE 2 concentrations. RESULTS: The mean IRS was higher in the epithelium of mucinous vs nonmucinous cysts for COX-2 (6.1 ± 4.7 vs 3.2 ± 2.8, P = 0.01) and cPLA2 (6.9 ± 3.0 vs 2.9 ± 2.9, P < 0.001). Cyst epithelial COX-2 expression was higher in mucinous cysts with low-grade dysplasia vs those with high-grade dysplasia or invasive carcinoma (IRS 8.0 ± 3.9 vs 1.5 ± 2.9, P < 0.001), whereas the opposite was found for cPLA2 (6.2 ± 3.0 vs 8.6 ± 2.3, P = 0.005). Cyst fluid PGE 2 concentrations did not correlate with either the IRS or a history of low- to moderate-dose ASA use. CONCLUSIONS: COX-2 and cPLA2 are overexpressed in the epithelium of mucinous pancreatic cysts. COX-2 and/or cPLA2 inhibition might prevent the emergence or progression of mucinous pancreatic cysts, but higher doses of ASA or nonsteroidal anti-inflammatory drugs may be necessary to substantially inhibit cyst epithelial COX-2 activity.

Marine omega‐3 polyunsaturated fatty acids (MO3PUFAs) have anticancer properties and may improve colon cancer survival. However, it remains unknown whether the benefit differs by tumor molecular subtype. We examined data from a phase III randomized trial of FOLFOX or FOLFOX + cetuximab among 1,735 stage III colon cancer patients who completed a dietary questionnaire at enrollment. Multivariable hazard ratios and 95% confidence intervals (CIs) were calculated for the association between MO3PUFA and disease‐free survival (DFS) and overall survival according toKRASandBRAFV600Emutations and DNA mismatch repair (MMR) status. Higher MO3PUFA intake was associated with improved 3‐year DFS forKRASwild‐type tumors (77%vs. 73%; HR: 0.84; 95% CI: 0.67–1.05) but notKRAS‐mutant tumors (64%vs. 70%; HR: 1.30; 95% CI: 0.97–1.73;Pinteraction= 0.02). Similar heterogeneity was found by MMR (Pinteraction= 0.14): higher MO3PUFA was associated with better 3‐year DFS for tumors with deficient MMR (72%vs. 67%) but not proficient MMR (72%vs. 72%). No heterogeneity was found byBRAFV600Emutation. Similar findings were obtained for overall survival. In conclusion, we found a suggestive beneficial association between higher MO3PUFA intake and improved survival among stage III colon cancer patients with wild‐typeKRASand deficient MMR. Given the relatively small number of cases with tumor molecular assessments, further studies, preferably through pooled analyses of multiples cohorts, are needed to validate our findings.

Abstract The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling—from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold “Cancer Interception” initiative.

Abstract Background: Immunotherapy targeting tumor-associated antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a relatively non-invasive and non-toxic prevention strategy, and because of the specificity of the immune response and its long-term memory, the potential for prolonged protection. In a double-blind randomized trial in patients with a diagnosis of advanced colorectal adenomas within the previous year, we are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC (Hiltonol®) as an adjuvant, for its immunogenicity and effect on colorectal adenoma recurrence at follow up colonoscopy. Aim: We report on a primary endpoint, MUC1 immunogenicity at week 12 (following vaccine or placebo administration at 0, 2, and 10 weeks), and on determinants of the immune response and vaccine toxicity. Methods: Subjects with an advanced adenoma (defined as ≥1cm, tubulovillous or villous histology, or with HGD) were randomized. Response to the vaccine was assessed by monitoring IgG anti-MUC1 antibody titer ratio; defined as t12/t0, where t0 is the initial titer measured prior to vaccination, and t12 is the titer drawn at 12 weeks. A ratio of 2.0 was used as the primary definition of a significant immune response. T Regulatory and myleoid derived suppressor cell (MDSC) levels at baseline were assessed in relation to vaccine response. Adverse events (AEs) were recorded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results: 102 subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. Subjects had a mean age of 59.4±7.0 (range 40-70) years, 60.8% were male, 88.2% were white, and 18.6% Hispanic or Latino. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of patients receiving vaccine (ratio range 2.9-17.3), vs. 0/50 in placebo group (P=.0001), and was ≥1.5 in 19/52 (36.5%) of patients receiving vaccine compared to 1/50 (2%) in placebo group (P&lt;.0001). In the vaccinated group, the IgG ratio was ≥2.0 in 45% of women (9/20) vs. 12.5% of men (4/32) (P=0.009) and ≥1.5 in 55% of women (11/20) vs. 25% of men (8/32) (P=0.03). In the vaccinated group, reduced levels of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) pre-vaccination were associated with response, 0.2±0.1 among responders (n=13) vs. 0.8±1.1 among non-responders (N=39) (p=0.0006) whereas monocytic MDSC and T regulatory cells (CD4+CD25, Foxp3) were not. There were no grade 3 adverse events (AE) possibly or probably related to the vaccine. The most common AE was an injection site reaction (grade 1 or 2) which occurred in 80.8% (n=42/52) in vaccine group vs. 6.0% in the placebo group (3/50). Conclusions: Subjects with an advanced adenoma receiving MUC1 vaccine compared with a placebo are significantly more likely to develop an anti-IgG MUC1 immune response at 12 weeks. Women and subjects with lower circulating PMN-MDSC levels at baseline were more likely to respond. The vaccine was well tolerated. Follow up for the effect of the vaccine on adenomatous polyp recurrence is ongoing. Citation Format: Robert E. Schoen, Lisa A. Boardman, Marcia Cruz-Correa, Ajay Bansal, Pamela L. Beatty, David Kastenberg, Chin Hur, Lynda Dzubinski, Luz Rodriguez, Andres Salazar, John McKolanis, Drew Seisler, Nathan R. Foster, May-Yin Polley, Paul J. Limburg, Olivera J. Finn. Randomized, double-blind, placebo-controlled immunoprevention trial with MUC1 vaccine in patients with newly diagnosed advanced adenomas [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 LB-305.

AbstractBackground: Prior studies have supported an inverse association between physical activity and colon cancer risk and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes.Methods: Before treatment arm randomization (FOLFOX or FOLFOX + cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N = 1,992). Using multivariable Cox models, we calculated HRs for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS).Results: Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 [95% confidence interval (CI), 0.69–0.99] and 0.76 (95% CI, 0.63–0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 versus T4 tumors (Pinteraction = 0.03).Conclusions: These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes.Impact: Our findings support further research on whether colon cancer survival may be enhanced by physical activity. Cancer Epidemiol Biomarkers Prev; 27(6); 696–703. ©2018 AACR.