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Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide

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Abstract

Tamoxifen and fenretinide have been extensively studied and exhibit breast cancer-preventing activity. We aimed to assess their effect on sex hormones, sex hormone binding globulin (SHBG) and retinol, and their association with mammographic density (MD) and breast cancer events. In a double-blind, placebo-controlled trial, premenopausal women at risk for breast cancer were randomized to tamoxifen 5 mg/day, fenretinide, both agents, or placebo for 2 years. We measured MD and circulating concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, testosterone, androstenedione, dehydro-epiandrosteronesulfate, prolactin, SHBG, and retinol at baseline and on yearly intervals. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models. Low-dose tamoxifen markedly and enduringly increased SHBG, whereas the increases in testosterone, estradiol, and prolactin and reduction in LH weakened after 1 year. Fenretinide increased testosterone and androstenedione and decreased retinol. MD correlated directly with SHBG and inversely with retinol. After a median follow-up of 12 years, the 10-year cumulative incidence of breast cancer events was 37 % in women with SHBG ≤ 59.3 nmol/L, 22 % in women with SHBG between 59.3 and 101 nmol/L, and 19 % in women with SHBG > 101 nmol/L (P = 0.018). The difference among SHBG tertiles remained statistically significant at multivariable analysis: HR = 2.26 (95 % CI 1.04, 4.89) for the lowest versus the highest tertile. We conclude that low-dose tamoxifen or fenretinide exhibits favorable hormonal profiles as single agents, further supporting their administration for prevention of breast cancer in premenopause. Notably, SHBG levels were inversely associated with breast neoplastic events.

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Abbreviations

MD:

Mammographic density

SHBG:

Sex hormone binding globulin

IEN:

Intraepithelial neoplasia

LH:

Luteinizing hormone

FSH:

Follicle-stimulating hormone

DHEA-S:

Dehydro-epiandrosteronesulfate

BMI:

Body mass index

IGF-I:

Insulin-like growth factor-I

DIN:

Ductal intraepithelial neoplasia

LIN:

Lobular intraepithelial neoplasia

EPIC:

European Prospective Investigation into Cancer and Nutrition

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Acknowledgments

The study was supported by the National Cancer Institute (grant No CA-77188), the Italian Foundation for Cancer Research (FIRC), a regional grant (1068/2005) on second tumors from the Associazione Italiana per la Ricerca sul Cancro (AIRC), and by the Italian Health Ministry, contracts RFPS-2006-1-339898 and RFPS-2006-1-339856 “Progetto Integrato Oncologia”.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy

    Harriet Johansson, Bernardo Bonanni, Aliana Guerrieri-Gonzaga, Massimiliano Cazzaniga, Davide Serrano, Debora Macis & Antonella Puccio

  2. Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

    Sara Gandini

  3. Division of Laboratory Medicine, European Institute of Oncology, Milan, Italy

    Maria Teresa Sandri

  4. Medical Oncology, Ospedale S. Bortolo, Vicenza, Italy

    Marcella Gulisano

  5. Chemoprevention Unit, Istituto Nazionale dei Tumori, Milan, Italy

    Franca Formelli

  6. Medical Oncology Unit, E.O. Galliera Hospital, Genoa, Italy

    Andrea DeCensi

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  1. Harriet Johansson
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  2. Bernardo Bonanni
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  3. Sara Gandini
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  10. Marcella Gulisano
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  11. Franca Formelli
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Correspondence to Harriet Johansson.

Appendix

Appendix

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Table 4 Least square means of biomarkers by time and treatments groups
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Johansson, H., Bonanni, B., Gandini, S. et al. Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide. Breast Cancer Res Treat 142, 569–578 (2013). https://doi.org/10.1007/s10549-013-2768-7

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