A Pilot Study Comparing the Effect of Flaxseed, Aromatase Inhibitor, and the Combination on Breast Tumor Biomarkers
A Pilot Study Comparing the Effect of Flaxseed, Aromatase Inhibitor, and the Combination on Breast Tumor Biomarkers
Year: 2014
Authors: McCann, S.E. Edge, S.B. Hicks, D.G. Thompson, L.U. Morrison, C.D. Fetterly, G. Andrews, C. Clark, K.
Publication Name: Nutr. Cancer
Publication Details: Volume 66; Issue 4; Pages 566 – 575
Abstract:
Use of complementary approaches is common among breast cancer survivors. Potential interactions between aromatase inhibitors (AI) and high phytoestrogen foods, such as flaxseed (FS), are not often described. We conducted a pilot 2 by 2 factorial, randomized intervention study between tumor biopsy and resection, in 24 postmenopausal women with estrogen receptor positive (ER plus) breast cancer, to assess the effects of FS and anastrozole, and possible interactions between them, on serum steroid hormone and tumor related characteristics associated with long term survival. The effect of each treatment vs. placebo on outcomes was determined by linear regression adjusting for pretreatment measure, stage, and grade. Although not statistically significant, mean ER beta expression was approximately 40 per cent lower from pre to post intervention in the FS plus AI group only. We observed a statistically significant negative association for androstenedione in the FS plus AI group vs. placebo and for DHEA with AI treatment. Enterolactone excretion was much lower in the FS plus AI group compared to the FS group. Our results do not support strong effects of FS on AI activity for selected breast tumor characteristics or serum steroid hormone levels but suggest AI therapy might reduce the production of circulating mammalian lignans from FS. (Authors abstract)
For estrogen-receptor positive tumors, antiestrogen therapy has been considered standard of care for breast cancer. The goal of endocrine treatment is to prevent access of the tumor to estrogen, either through blocking the interaction of the estrogen receptor with coregulatory proteins in tumor cells (Tamoxifen), or through a reduction or elimination of endogenous estrogen production (aromatase inhibitors; AI). AI block the enzyme aromatase that catalyzes the conversion of androgens into estrogens, the primary source of endogenous estrogens in postmenopausal women.
Flaxseed (FS) lignans are considered phytoestrogens, naturally occurring diphenolic compounds structurally similar to endogenous estrogens and Tamoxifen. The major circulating lignan, enterolactone, is considered a weak estrogen compared to estradiol. In human and experimental studies, FS ingestion has been shown to affect both endocrine and growth factor pathways by modifying steroid hormone metabolism, modifying IGF and EGFR, and inhibiting aromatase and 17beta hydroxysteroid dehydrogenase. Lignans inhibit cell proliferation in both estrogen receptor positive and negative cell lines, reduce tumor growth and metastasis in a number of animal models, and work synergistically with Tamoxifen to reduce tumor growth.
Use of concomitant hormonal treatments is contraindicated during treatment with anastrozole, as these may reduce the efficacy of the drug. Because the phytoestrogens in FS can influence many of the same biologic pathways affected by antihormonal agents, the potential for physiologic effects exists and diet drug interactions are possible. Given the role of AIs in adjuvant treatment of breast cancer and the prevalent use of supplements such as FS, this pilot 2 by 2 factorial, randomized intervention study between tumor biopsy and resection, in postmenopausal women diagnosed with estrogen receptor positive (ER plus) breast cancer, was conducted to assess the effects of FS and the aromatase inhibitor, anastrozole, on a number of steroid hormone and tumor-related characteristics associated with long term survival, and to investigate the potential interaction between FS and anastrozole on these biomarkers.
In this small clinical trial, little evidence of an interaction between FS and a commonly prescribed AI, anastrozole, in the modification of several breast tumor characteristics related to prognosis or in serum hormone levels was found. Expected reductions in DHEA in association with AI treatment, as well as a significant decrease associated with AI and an interaction between FS plus AI for a reduction in androstenedione was shown. It is unclear why there was no effect of AI or FS alone on markers previously shown to be affected by these agents, such as ki67.
However, a fairly substantial, although not statistically significant, effect of AI on urinary lignan excretion in the FS plus AI group compared to the FS only group was reported. The mechanism behind this reduction in urinary lignan excretion is unclear. A 40 per cent decrease in expression of ER beta from pre to post intervention for women in the FS plus AI treatment group only. DHEA activates estrogen receptors alpha and beta. In this study, both AI and FS plus AI treatments reduced DHEA production with comparable effects.
A large body of experimental data and limited human data support the potential for FS to be used in breast cancer chemoprevention and treatment, but given the capacity for FS lignans to inhibit aromatase, it was hypothesized that food drug interactions were possible and that the action of aromatase could be dampened. In this small pilot study, we did not observe an effect of FS on AI activity with regards to selected breast tumor characteristics, growth hormone, or serum steroid hormone levels, although the sample size was likely too small to show small effects. There was a suggestion that AI therapy might reduce the production of circulating mammalian lignans from FS. This dampening of lignan production by AIs would have implications for the use of FS as a potential chemopreventive natural agent as the effective dose would be limited. (Editors comments)
For estrogen-receptor positive tumors, antiestrogen therapy has been considered standard of care for breast cancer. The goal of endocrine treatment is to prevent access of the tumor to estrogen, either through blocking the interaction of the estrogen receptor with coregulatory proteins in tumor cells (Tamoxifen), or through a reduction or elimination of endogenous estrogen production (aromatase inhibitors; AI). AI block the enzyme aromatase that catalyzes the conversion of androgens into estrogens, the primary source of endogenous estrogens in postmenopausal women.
Flaxseed (FS) lignans are considered phytoestrogens, naturally occurring diphenolic compounds structurally similar to endogenous estrogens and Tamoxifen. The major circulating lignan, enterolactone, is considered a weak estrogen compared to estradiol. In human and experimental studies, FS ingestion has been shown to affect both endocrine and growth factor pathways by modifying steroid hormone metabolism, modifying IGF and EGFR, and inhibiting aromatase and 17beta hydroxysteroid dehydrogenase. Lignans inhibit cell proliferation in both estrogen receptor positive and negative cell lines, reduce tumor growth and metastasis in a number of animal models, and work synergistically with Tamoxifen to reduce tumor growth.
Use of concomitant hormonal treatments is contraindicated during treatment with anastrozole, as these may reduce the efficacy of the drug. Because the phytoestrogens in FS can influence many of the same biologic pathways affected by antihormonal agents, the potential for physiologic effects exists and diet drug interactions are possible. Given the role of AIs in adjuvant treatment of breast cancer and the prevalent use of supplements such as FS, this pilot 2 by 2 factorial, randomized intervention study between tumor biopsy and resection, in postmenopausal women diagnosed with estrogen receptor positive (ER plus) breast cancer, was conducted to assess the effects of FS and the aromatase inhibitor, anastrozole, on a number of steroid hormone and tumor-related characteristics associated with long term survival, and to investigate the potential interaction between FS and anastrozole on these biomarkers.
In this small clinical trial, little evidence of an interaction between FS and a commonly prescribed AI, anastrozole, in the modification of several breast tumor characteristics related to prognosis or in serum hormone levels was found. Expected reductions in DHEA in association with AI treatment, as well as a significant decrease associated with AI and an interaction between FS plus AI for a reduction in androstenedione was shown. It is unclear why there was no effect of AI or FS alone on markers previously shown to be affected by these agents, such as ki67.
However, a fairly substantial, although not statistically significant, effect of AI on urinary lignan excretion in the FS plus AI group compared to the FS only group was reported. The mechanism behind this reduction in urinary lignan excretion is unclear. A 40 per cent decrease in expression of ER beta from pre to post intervention for women in the FS plus AI treatment group only. DHEA activates estrogen receptors alpha and beta. In this study, both AI and FS plus AI treatments reduced DHEA production with comparable effects.
A large body of experimental data and limited human data support the potential for FS to be used in breast cancer chemoprevention and treatment, but given the capacity for FS lignans to inhibit aromatase, it was hypothesized that food drug interactions were possible and that the action of aromatase could be dampened. In this small pilot study, we did not observe an effect of FS on AI activity with regards to selected breast tumor characteristics, growth hormone, or serum steroid hormone levels, although the sample size was likely too small to show small effects. There was a suggestion that AI therapy might reduce the production of circulating mammalian lignans from FS. This dampening of lignan production by AIs would have implications for the use of FS as a potential chemopreventive natural agent as the effective dose would be limited. (Editors comments)
