Melissa May

Circulating fibroblast growth factor-23 is associated with increased risk for metachronous colorectal adenoma

Background: Fibroblast growth factor-23 (FGF-23) is a phosphaturic peptide and a key component of an endocrine feedback loop along with the hormonal vitamin D metabolite 1,25(OH)2D. Vitamin D has been shown to be inversely related to colorectal neoplasia; therefore, we hypothesized that the effect of FGF-23 on vitamin D metabolite concentrations could have implications for the risk of colorectal neoplasia. Materials and Methods: The purpose of this study was to prospectively evaluate the association between circulating concentrations of FGF-23 and the risk of metachronous (recurrent) colorectal adenomas. FGF-23 levels were assessed in 100 male and female participants from the Ursodeoxycholic Acid Trial, 50 of whom had a metachronous colorectal adenoma and 50 who did not. Results: Compared to the lowest tertile of FGF-23, the adjusted odds ratios (95% CIs) for the second and third tertiles were 2.80 (0.94 to 8.31) and 3.41 (1.09 to 10.67), respectively (P-trend=.03). In a linear regression model, there was also a statistically significant inverse relationship between FGF-23 and 1,25(OH)2D (β-coefficient=–1.2; P=.001). In contrast, no statistically significant trend was observed between FGF-23 and 25(OH)D concentrations (β-coefficient=0.55; P=.10). Conclusions: The current work presents novel preliminary evidence of a relationship between FGF-23 and the risk for colorectal neoplasia. FGF-23 activity may be mediated through biologic effects on individual serum and colonic 1,25(OH)2D levels, or it may be independent from the vitamin D pathway. Further studies in larger populations are necessary for confirmation and expansion of these hypothesis-generating results.

Abstract B36: Circulating FGF-23 is associated with metachronous colorectal adenomas

Fibroblast growth factor-23 (FGF-23) is a phosphaturic peptide and a key component of an endocrine feedback loop with the hormonal vitamin D metabolite 1,25(OH)2D. It is both induced by and represses the synthesis of 1,25(OH)2D in a concerted effort to maintain both calcium and phosphate homeostasis. Vitamin D has been shown to be inversely related to colorectal neoplasia; therefore, we hypothesized that the effect of FGF-23 on 1,25(OH)2D concentrations could have implications for the risk of colorectal neoplasia. The purpose of this study was to prospectively evaluate the association between circulating concentrations of FGF-23 and odds of metachronous (recurrent) colorectal adenomas, the precursors to colorectal cancer. FGF-23 levels were assessed in 100 male and female participants from the Ursodeoxycholic Acid trial, 50 of whom had a metachronous colorectal adenoma and 50 who did not. Compared to the lowest tertile of FGF-23, the adjusted ORs (95% CIs) for the second and third tertiles were 2.80 (0.94-8.31) and 3.41 (1.09-10.67), respectively; a significant trend was shown for the relationship between FGF-23 concentration and odds for metachronous adenoma (p=0.03). In addition, there was a statistically significant inverse relationship between FGF-23 and 1,25(OH)2D, with those in the highest tertile of circulating 1,25(OH)2D having the lowest concentrations of FGF-23. Levels of FGF-23 were 81.4 + 36.6 RU/ml, 75.0 + 34.5 RU/ml, 55.7 + 15.8 RU/ml for low, medium, and high tertiles of 1,25(OH)2D, respectively (p-trend=0.001). In contrast, no statistically significant trend was observed between FGF-23 and 25(OH)D concentrations, with FGF-23 levels of 66.4 + 223.4 RU/ml, 69.1 + 38.6 RU/ml, and 76.1 + 40.7 RU/ml among participants who were vitamin D insufficient ( 20 ng/ml and 30 ng/ml); p-trend=0.28. This work provides novel evidence of an association between FGF-23 and risk for colorectal neoplasia, and the results support an important role for FGF-23 as a potential risk biomarker of early colorectal carcinogenesis. The effects of FGF-23 may be mediated through biologic effects on individual 1,25(OH)2D levels. Further studies in larger populations are necessary for confirmation of these results. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B36.

Abstract A119: Effect of weight‐bearing exercise on circulating biomarkers in breast cancer survivors

Breast cancer patients generally demonstrate a gain in body fat mass accompanied by loss of lean mass (i.e. muscle) during cancer therapy (Demark‐Wahnefried et al, J. Clin Oncol, 2001). These changes may lead to adverse metabolic and inflammatory phenotypes. The objective of this pilot study was to evaluate changes in metabolic, inflammatory, and growth factor biomarkers among breast cancer survivors following 8 weeks of supervised resistance training combined with self‐reported cardiovascular training. No diet or weight loss component was included in the intervention. Twenty‐seven breast cancer survivors (78.3% Caucasian, mean age 56.5 ± 8.1 yrs, mean BMI 29.8 ± 4.4kg/m 2 ) who were on average 5 years post‐cancer treatment were recruited to participate in a prospective behavioral intervention trial to test the hypothesis that weight bearing activity including stretching, resistance, balance, and aerobic training would improve select metabolic and inflammatory indicators over an 8 week period. Height, weight, body composition (dual X‐ray absorptiometry), fasting plasma glucose, insulin, IL‐6, CRP, IL‐1Ra, and IGF‐1 were measured at baseline and 8 weeks. IL‐6, IL‐1Ra and IGF‐1 were analyzed using high sensitivity ELISA and glucose was measured by a glucose oxidase‐peroxide reaction; insulin and CRP testing were performed by the local hospital clinical laboratory. The homeostasis model of insulin resistance was computed (HOMA‐IR) from glucose and insulin values. Eighty‐one percent of the sample completed the 8‐week intervention. Among completers (n=22) there was no significant change in body weight. Inflammatory response, as assessed using IL‐1Ra, was improved (76.75 ± 161.39, p Breast cancer survivors participating in a pilot, short‐term structured physical activity intervention targeting resistance training, in the absence of diet or weight change, demonstrated a significant improvement in the anti‐inflammatory biomarker IL‐1Ra without concomitant increases in pro‐inflammatory biomarkers, IL‐6 and CRP. Larger studies with sufficient sample size to detect statistically significant differences should be pursued; combining structured exercise with diet to support weight reduction may also be superior and should be evaluated. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A119.

Abstract CN04-03: Phase 1b sulindac study for women at high risk for breast cancer

CN04-03 Background Regular use of non steroidal anti-inflammatory agents (NSAIDs) has been associated with reduced risk of breast cancer. The breast specific activity of each of the numerous NSAID agents and their relative potency to prevent breast cancer remains unknown. Sulindac, a non selective NSAID with pro apoptotic activity is a strong candidate for chemoprevention. Objective and Methods To assess concentrations of sulindac and its metabolites as well as their effects on known molecular markers in nipple aspirate fluid (NAF) in 15 subjects receiving 150 mg once daily and 15 subjects receiving 150 mg twice daily sulindac. NAF and serum samples were collected before and after 6 weeks of sulindac dosing. Results Sulindac and sulfide were detectable in 57.7% of NAF samples with sulfone detectable in 11.6%. There were no statistically significant differences between sulindac or sulfide levels in NAF by dose. There was a significant positive correlation between NAF sulindac and NAF sulfide levels. NAF 13,14-dihydro-15-keto prostaglandin A2 (PGEM), a stable derivative of prostaglandins, exhibited a non significant trend towards decreased levels (p =0.1). Serum levels of sulindac, but not NAF sulindac, was correlated with a decrease in NAF PGEM levels (p=0.03). The NSAID inducible protein, growth differentiation factor GDF-15, showed a borderline significant trend towards higher levels in NAF in the 300 mg daily group (p = 0.07). Serum CRP levels were decreased with sulindac exposure with the greatest decrease observed among those women with elevated CRP levels at baseline. Conclusion Sulindac and its sulfide metabolites partition to the breast and are detectable in NAF. Sulindac exposure was associated with a trend towards reduction in PGEM that was correlated with serum levels of sulindac. GDF-15 levels increased in the high dose group. NAF levels of PGEM and GDF-15 may prove useful as NSAID response biomarkers if for larger efficacy based intervention studies in breast cancer prevention. Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN04-03.