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

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Abstract

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.

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Acknowledgements

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.

Funding

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.

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Authors and Affiliations

  1. Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona, 3950 S. Country Club, Suite 3210, Tucson, AZ, 85714, USA

    Cynthia A. Thomson

  2. University of Arizona Cancer Center, Tucson, AZ, USA

    Cynthia A. Thomson, H. H. Sherry Chow, Betsy C. Wertheim, Denise J. Roe, Pavani Chalasani & Jean-Philippe Galons

  3. Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA

    Denise J. Roe

  4. Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA

    Alison Stopeck & Patricia A. Thompson

  5. Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

    Gertraud Maskarinec

  6. Department of Medical Imaging, College of Medicine, University of Arizona, Tucson, AZ, USA

    Maria Altbach & Jean-Philippe Galons

  7. Departments of Radiology, Psychiatry, School of Medicine, Stony Brook University, Stony Brook, NY, USA

    Chuan Huang

  8. Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA

    Meghan B. Strom

  9. Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, NY, USA

    Patricia A. Thompson

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Thomson, C.A., Chow, H.H.S., Wertheim, B.C. et al. A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Res Treat 165, 97–107 (2017). https://doi.org/10.1007/s10549-017-4292-7

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