Prevention, Early Detection and Risk Stratification

Evaluation of Diindolymethane supplementation to modulate tamoxifen efficacy in breast cancer: A randomized, placebo-controlled trial testing efficacy of DIM + TAM in modifying breast density, MRI, sex hormones, tamoxifen metabolites in breast cancer survivors

NCI • R01 CA149417-01A1
Cynthia Thomson, PhD, RD, CSO

The treatment of breast cancer has progressed rapidly in the past 20-30 years, particularly for women diagnosed with estrogen responsive disease. Yet, women diagnosed with breast cancer remain at an increased risk for recurrent cancer for the remainder of their lives. TAM has served as the primary therapeutic agent for the treatment of estrogen receptor positive disease for the past decade and TAM is also a common drug therapy used in the primary prevention setting by women at increased genetic risk for disease. While the therapeutic use of TAM has been clearly demonstrated, there remain concerns regarding drug resistance as well as toxicity. Elevated circulating estradiol, lack of hot flash response and lower serum endoxifen levels have all been associated with reduced clinical response to TAM and endometrial toxicity remains a primary concern11. Strategies to enhance the efficacy of TAM while at the same time targeting a reduction in toxicity are needed. Here we propose a novel approach in addressing these clinical concerns using a bioactive food-derived compound in combination with TAM.

Specific Aims
To test our primary hypothesis, we propose a randomized, double-blind, placebo-controlled trial among 170 premenopausal treated with TAM in which women are randomized to receive 150 mg oral DIM or Placebo for a period of 18 months.

1. Assess change in breast density from baseline to 18 months post-intervention using mammogram-based breast density measures as well as a novel, quantitative fat-water ratio breast magnetic resonance imaging (FWR-MRI).
2. Evaluate the effect of 150 mg daily DIM on serum steroid hormones (estrogen, sex hormone binding globulin (SHBG)) and urinary 2-hydroxyestrone:16α-hydroxyestrone (2OHE1:16αOHE1) ratio as well as serum TAM metabolites (endoxifen) in premenopausal women treated with TAM.
3. Evaluate TAM-associated endometrial toxicity using self-reported vaginal bleeding and vaginal ultrasound in women receiving DIM (150 mg DIM daily for 18 months) in combination with TAM.

TAM is commonly prescribed for breast cancer treatment in premenopausal women. Direct demonstration of a greater risk modifying activity and/or reduced TAM toxicity TAM + DIM versus TAM alone using pharmacologic dosing of the bioavailable BioResponse™ DIM would substantiate the clinical potential of DIM to improve health outcomes in this at-risk group.

Preliminary evidence supports an enhancing effect of cruciferous for the prevention of breast cancer recurrences in women on TAM. The specific mechanisms for this are not well characterized. We speculate that, based on strong pre-clinical evidence, the effects of diindolylmethane (DIM), a bioactive of cruciferous vegetables with demonstrated chemopreventive properties in animal models, on select breast cancer risk factors. Specifically, we seek to demonstrate that exposure to TAM + DIM (vs TAM alone) will result in greater reduction in breast density, a reduction in estrogen as well as greater C-2 hydroxylation and a potential elevation in the levels of endoxifen as the active metabolite of TAM. We also plan to evaluate the potential of DIM to reduce the endometrial toxicity associated with TAM use. Research to identify evidence-based diet-related strategies to significantly improve the efficacy or reduce toxicity of existing pharmaceuticals is an understudied area of translational research 

This is a phase II trial of 150 mg DIM given daily for 18 months in women taking TAM to test the primary study hypothesis that DIM given orally in capsular form will be associated with a greater reduction in breast density as well as modulation of circulating hormone levels to reduce estrogen exposure. Further, these proposed improvements in breast cancer risk factors with TAM+DIM (as compared to TAM alone) will be accompanied by a reduction in TAM toxicity related to endometrial health.