A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen

Breast Cancer Res Treat. 2017 Aug;165(1):97-107. doi: 10.1007/s10549-017-4292-7. Epub 2017 May 30.


Purpose: Diindolylmethane (DIM), a bioactive metabolite of indole-3-carbinol found in cruciferous vegetables, has proposed cancer chemoprevention activity in the breast. There is limited evidence of clinically relevant activity of DIM or long-term safety data of its regular use. A randomized, double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined use of BioResponse DIM® (BR-DIM) with tamoxifen.

Methods: Women prescribed tamoxifen (n = 130) were randomly assigned oral BR-DIM at 150 mg twice daily or placebo, for 12 months. The primary study endpoint was change in urinary 2/16α-hydroxyestrone (2/16α-OHE1) ratio. Changes in 4-hydroxyestrone (4-OHE1), serum estrogens, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites were assessed.

Results: Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. BR-DIM increased the 2/16α-OHE1 ratio (+3.2 [0.8, 8.4]) compared to placebo (-0.7 [-1.7, 0.8], P < 0.001). Serum SHBG increased with BR-DIM compared to placebo (+25 ± 22 and +1.1 ± 19 nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed. Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen) were reduced in women receiving BR-DIM versus placebo (P < 0.001). Minimal adverse events were reported and did not differ by treatment arm.

Conclusion: In patients taking tamoxifen for breast cancer, daily BR-DIM promoted favorable changes in estrogen metabolism and circulating levels of SHBG. Further research is warranted to determine whether BR-DIM associated decreases in tamoxifen metabolites, including effects on endoxifen levels, attenuates the clinical benefit of tamoxifen.

Trial registration: ClinicalTrials.gov NCT01391689.

Keywords: Breast cancer; Diindolylmethane; Tamoxifen.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / blood
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor* / blood
  • Biomarkers, Tumor* / urine
  • Breast Neoplasms / blood
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / urine
  • Double-Blind Method
  • Female
  • Humans
  • Hydroxyestrones / blood
  • Hydroxyestrones / urine
  • Indoles / administration & dosage*
  • Indoles / adverse effects
  • Mammography
  • Middle Aged
  • Sex Hormone-Binding Globulin / metabolism
  • Tamoxifen / administration & dosage*
  • Tamoxifen / adverse effects
  • Tamoxifen / blood
  • Time Factors
  • Treatment Outcome


  • Biomarkers, Tumor
  • Hydroxyestrones
  • Indoles
  • Sex Hormone-Binding Globulin
  • Tamoxifen
  • 16-hydroxyestrone
  • 4-hydroxyestrone
  • 3,3'-diindolylmethane
  • 2-hydroxyestrone

Associated data

  • ClinicalTrials.gov/NCT01391689