Breast Cancer Research and Treatment

, Volume 165, Issue 1, pp 97–107 | Cite as

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

  • Cynthia A. ThomsonEmail author
  • H. H. Sherry Chow
  • Betsy C. Wertheim
  • Denise J. Roe
  • Alison Stopeck
  • Gertraud Maskarinec
  • Maria Altbach
  • Pavani Chalasani
  • Chuan Huang
  • Meghan B. Strom
  • Jean-Philippe Galons
  • Patricia A. Thompson
Clinical trial



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.


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.


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.


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: NCT01391689.


Breast cancer Diindolylmethane Tamoxifen 



The investigators wish to acknowledge the contributions of Julie West, study coordinator, Amelia Lobos, study agent manager, Catherine Cordova for performing the estrogen assays and Jean-Phillippe Galons and Jie Ding for assisting with FWR-MRI image processing. The investigators also would like to thank Drs. Steven Stratton, Robert Livingston, and Chiu-Hsieh (Paul) Hsu for serving as members of the ad hoc Data and Safety Monitoring Committee. This research supported by National Institutes of Health, National Cancer Institute grant numbers CAT R01 CA149417 and CCSG-P30CA023074 as well as a research grant from the Academy of Nutrition and Dietetics, Oncology Nutrition Practice Group.


This work was support by The National Cancer Institute (NCI) at the National Institutes of Health (NIH) (CAT R01 CA149417 and CA161534), as well as NCI funding provided to The University of Arizona Comprehensive Cancer Center Support Grant (CCSG-P30CA023074) including support of the Behavioral Measurements and Interventions, Analytical Chemistry, Cancer Imaging, and Biostatistics Shared Resources as well as the Clinical Trials Office and the Data Safety and Monitoring Board.

Compliance with ethical standards

Conflicts of interest

The authors have no conflicts of interest to disclose.

Supplementary material

10549_2017_4292_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 17 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Cynthia A. Thomson
    • 1
    • 2
    Email author
  • H. H. Sherry Chow
    • 2
  • Betsy C. Wertheim
    • 2
  • Denise J. Roe
    • 2
    • 3
  • Alison Stopeck
    • 4
  • Gertraud Maskarinec
    • 5
  • Maria Altbach
    • 6
  • Pavani Chalasani
    • 2
  • Chuan Huang
    • 7
  • Meghan B. Strom
    • 8
  • Jean-Philippe Galons
    • 2
    • 6
  • Patricia A. Thompson
    • 4
    • 9
  1. 1.Department of Health Promotion SciencesMel and Enid Zuckerman College of Public Health, University of ArizonaTucsonUSA
  2. 2.University of Arizona Cancer CenterTucsonUSA
  3. 3.Department of Epidemiology and BiostatisticsMel and Enid Zuckerman College of Public Health, University of ArizonaTucsonUSA
  4. 4.Stony Brook Cancer CenterStony Brook UniversityStony BrookUSA
  5. 5.Cancer Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluUSA
  6. 6.Department of Medical ImagingCollege of Medicine, University of ArizonaTucsonUSA
  7. 7.Departments of Radiology, Psychiatry, School of MedicineStony Brook UniversityStony BrookUSA
  8. 8.Department of Nutritional SciencesUniversity of ArizonaTucsonUSA
  9. 9.Department of Pathology, School of MedicineStony Brook UniversityStony BrookUSA

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