Skip to main content
SpringerLink
Log in

Chemoprevention of Breast Cancer with Fenretinide

  • Leading Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Chemoprevention of cancer represents a challenge for oncology during this new millennium. Substantial advances have been accomplished in the last decade, especially for primary and secondary prevention of breast cancer. In addition to tamoxifen, raloxifene and other selective estrogen receptor modulators, retinoids are among the most promising agents, given their ability to inhibit mammary carcinogenesis in preclinical models.

Fenretinide, the synthetic amide of retinoic acid, inhibits cell growth mostly through the induction of apoptosis with mechanisms which may partly involve the retinoid receptors. Because it has a favourable toxicological profile, fenretinide has been extensively investigated in clinical trials. A large randomised phase III trial for secondary breast cancer prevention has been recently carried out in Italy. Results showed a reduction of second breast malignancies in premenopausal women. In addition, a significant decrease of circulating insulin-like growth factor (IGF)-1, a known risk factor for premenopausal breast cancer, was observed after 1 year of fenretinide administration in premenopausal women with breast cancer.

Ongoing studies on the validation of the circulating IGF-1 as a surrogate endpoint biomarker of fenretinide activity and on the effectiveness of the combination with low dose tamoxifen may provide further insight into the future clinical application of fenretinide.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II

Similar content being viewed by others

References

  1. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998; 352: 930–42

    Article  Google Scholar 

  2. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351: 1451–67

    Article  Google Scholar 

  3. Crown J, O’Leary M. The taxanes: an update. Lancet 2000; 355: 1176–8

    Article  PubMed  CAS  Google Scholar 

  4. Kerlikowske K. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. J Natl Cancer Inst Monogr 1997; 22: 79–86

    PubMed  Google Scholar 

  5. Fisher B, Costantino JP, Wicherham DL, et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 1998 Sep 16; 90(18): 1371–88

    Article  PubMed  CAS  Google Scholar 

  6. Lippman SM, Brown PH. Tamoxifen prevention of breast cancer: an instance of the fingerpost [commentary]. J Natl Cancer Inst 1999 Nov 3; 91(21): 1809–19

    Article  PubMed  CAS  Google Scholar 

  7. Sporn MB, Newton DL. Chemoprevention of cancer with retinoids. Fed Proc 1979; 38: 2528–34

    PubMed  CAS  Google Scholar 

  8. Lippman SM, Lee JJ, Sabichi AL. Cancer chemoprevention: progress and promise. J Natl Cancer Inst 1998; 90: 1514–28

    Article  PubMed  CAS  Google Scholar 

  9. Cummings SR, Eckert S, Krueger KA, et al. The effect of Raloxifene on risk of breast cancer in postmenopausal women. Results from the MORE randomized trial. JAMA 1999 Jun 16; 281(23): 2189–97

    Article  PubMed  CAS  Google Scholar 

  10. Rhodes DJ, Hartmann LC, Perez EA. Breast cancer prevention trials. Curr Oncol Rep 2000; 2: 558–65

    Article  PubMed  CAS  Google Scholar 

  11. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 1996; 10: 940–54

    PubMed  CAS  Google Scholar 

  12. Sporn MB, Suh N. Chemoprevention of cancer. Carcinogenesis 2000; 21(3): 525–30

    Article  PubMed  CAS  Google Scholar 

  13. Spinella MJ, Dimitrovsky E. Aberrant retinoid signaling and breast cancer: the view from outside the nucleus [editorial]. J Natl Cancer Inst 2000; 92: 438–40

    Article  PubMed  CAS  Google Scholar 

  14. Fanjul A, Dawson Mi, Hobbs PD, et al. A new class of retinoids with selective inhibtion of AP-1 inhibits proliferation. Nature 1994; 372: 107–11

    Article  PubMed  CAS  Google Scholar 

  15. Lotan R, Xu X-C, Lippman SM, et al. Suppression of retinoic acid receptor-in premalignant oral lesions and its upregulation by isotretinoin. N Engl J Med 1995; 332: 1405–10

    Article  PubMed  CAS  Google Scholar 

  16. Sabichi Al, Hendricks DT, Bober MA, et al. Retinoic acid receptor-expression and growth inhibition of gynecologic cancer cells by the synthetic retinoid N-(4-hydroxyphenyl) retinamide. J Natl Cancer Inst 1998; 15: 597–605

    Article  Google Scholar 

  17. Xu X-C, Sneige N, Liu X, et al. Progressive decrease in nuclear retinoic acid receptor messenger RNA level during breast carcinogenesis. Cancer Res 1997; 57: 4992–6

    PubMed  CAS  Google Scholar 

  18. Widschwendter M, Berger J, Daxenbichler G, et al. Loss of retinoic acid receptor beta expression in breast cancer and morphologically normal adjacent tissue but not in the breast tissue distant from the cancer. Cancer Res 1997; 57: 4158–61

    PubMed  CAS  Google Scholar 

  19. Lin F, Xiao D, Kumar Kolluri S, et al. Unique anti-Activator Protein-1 activity of retinoic acid receptor. Cancer Res 2000; 60: 3271–80

    PubMed  CAS  Google Scholar 

  20. Shang Y, Baumrucker CR, Green M. Signal relay by retinoic acid receptor and in the retinoic acid-induced expression of insulin-like growth factor-binding protein-3 in breast cancer cells. J Biol Chem 1999; 274: 18005–10

    Article  PubMed  CAS  Google Scholar 

  21. Sporn MB, Dunlop NM, Newton DL, et al. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 1979; 35: 1332–8

    Google Scholar 

  22. Moon RC, Thompson HJ, Becci PJ, et al. N-(4-hydroxypheynl) retinamide), a new retinoid for prevention of breast cancer in the rat. Cancer Res 1979, 39: 1339–46

    PubMed  CAS  Google Scholar 

  23. Kelloff GJ, Crowell JA, Boone CW, et al.: Clinical development plan: N-(4-hydroxyphenyl)retinamide (4-HPR). J Cell Biochem 1994; 20 Suppl.: 176–96

    CAS  Google Scholar 

  24. Sheikh MS, Shao ZM, Li XS, et al. N-(4-hydroxyphenyl) retinamide (4-HPR) —mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma Carcinogenesis 1995; 16: 2477–86

    CAS  Google Scholar 

  25. Fanjul AN, Delia D, Pierotti MA, et al. 4-hydroxyphenyl-retinamide is a highly selective activator of retinoid receptors [published erratum appears in J Biol Chem 1996; 271: 33705]. J Biol Chem 1996; 271: 22441–6

    Article  PubMed  CAS  Google Scholar 

  26. Sun SY, Li W, Yue P, et al. Mediation of N-(4-hydroxyphenyl) retinamide-induced apoptosis in human cancer cells by different mechanisms. Cancer Res 1999; 59: 2493–8

    PubMed  CAS  Google Scholar 

  27. Lotan R. Retinoids and apoptosis: implications for cancer chemoprevention and therapy [editorial]. J Natl Cancer Inst 1995; 87: 1655–7

    Article  PubMed  CAS  Google Scholar 

  28. Oridate N, Suzuki S, Masahiro H, et al. Involvement of reactive oxygen species in N-(4-hydroxyphenyl)retinamide-induced apoptosis in cervical carcinoma cells. J Natl Cancer Inst 1997; 89: 1191–8

    Article  PubMed  CAS  Google Scholar 

  29. Herbert BS, Sanders BG, Kline K. N-(4-hydroxyphenyl) retinamide activation of transforming growth factor-beta and induction of apoptosis in human breast cancer cells. Nutr Cancer 1999; 34(2): 121–32

    Article  PubMed  CAS  Google Scholar 

  30. Sun SY, Yue P, Lotan R. Induction of apoptosis by N-(hydroxyphenyl)retinamide and its association with reactive oxygen species, nuclear retinoic acid receptors, and apoptosis-related genes in human prostate carcinoma cells. Mol Pharmacol 1999; 55: 403–10

    PubMed  CAS  Google Scholar 

  31. Bednarek A, Shilkaitis A, Green A, et al. Suppression of cell proliferation and telomerase activity in 4-(hydroxyphenyl) retinamide-treated mammary tumors. Carcinogenesis 1999 May; 20(5): 879–83

    Article  PubMed  CAS  Google Scholar 

  32. Jinno H, Steiner MG, Mehta RG, et al. Inhibition of aberrant proliferation and induction of apoptosis in HER-2/neu oncogene transformed human mammary epithelial cells by N-(4-hydroxyphenyl)retinamide. Carcinogenesis 1999 Feb; 20(2): 229–36

    Article  PubMed  CAS  Google Scholar 

  33. Rao GN, Ney E, Herbert NA. Effect of retinoid analogues on mammary cancer in transgenic mice bearing c-neu transfected breast cancer oncogene. Breast Cancer Res Treat 1998 Apr; 48: 265–71

    Article  PubMed  CAS  Google Scholar 

  34. Mehta RG, Moon RC, Hawthorne M, et al. Distribution of fenretinide in the mammary gland of breast cancer patients. Eur J Cancer 1991; 27(2): 138–41

    Article  PubMed  CAS  Google Scholar 

  35. Broet P, de la Rochefordiere A, Scholl SM, et al. Contralateral breast cancer: annual incidence and risk parameters. J Clin Oncol 1995; 13: 1578–83

    PubMed  CAS  Google Scholar 

  36. Formelli F, Carsana R, Costa A, et al. Plasma retinol reduction by the synthetic retinoid fenretinide: a one year follow-up study. Cancer Res 1989; 49: 6149–52

    PubMed  CAS  Google Scholar 

  37. Costa A, Malone W, Perloff M, et al. Phase I trial of fenretinide (HPR) in breast cancer patients. Eur J Cancer Clin Oncol 1989; 25: 805–9

    Article  PubMed  CAS  Google Scholar 

  38. Zujewski J, Pai L, Wakefield L, et al. Tamoxifen and Fenretinide in women with metastatic breast cancer. Breast Cancer Res Treat 1999; 57: 277–83

    Article  PubMed  CAS  Google Scholar 

  39. Cobleigh MA, Dowlatsahi K, Deutsch TA, et al. Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer. J Clin Oncol 1993; 11: 474–7

    PubMed  CAS  Google Scholar 

  40. Berni R, Formelli F. In vitro interaction of fenretinide with plasma retinol-binding protein and its functional consequences. FEBS Lett 1992; 308: 43–5

    Article  PubMed  CAS  Google Scholar 

  41. Lewis KC, Zech LA, Pheng JM. Effects of chronic administration of N-(4-hydroxyphenyl)retinamide (4-HPR) in rats on vitamin A metabolism in eye. Eur J Cancer 1996; 32A: 1803–8

    Article  PubMed  CAS  Google Scholar 

  42. Torrisi R, Parodi S, Fontana V, et al. Factors affecting plasma retinol decline during long-term administration of the synthetic retinoid fenretinide in breast cancer patients. Cancer Epidemiol Biomarkers Prev 1994; 3: 507–10

    PubMed  CAS  Google Scholar 

  43. Formelli F, Clerici M, Campa T, et al. Five-year administration of fenretinide of fenretinide: pharmacokinetics and effects on plasma retinol concentrations. J Clin Oncol 1993; 11: 2306–42

    Google Scholar 

  44. De Palo G, Camerini T, Marubini E, et al Chemoprevention trial of contralateral breast cancer with fenretinide. Rationale, design, methodology, organization, data management, statistics and accrual. Tumori 1997; 83: 884–94

    PubMed  Google Scholar 

  45. Veronesi U, De Palo G, Marubini E, et al. Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer. J Natl Cancer Inst 1999; 91: 1847–56

    Article  PubMed  CAS  Google Scholar 

  46. De Palo G, Veronesi U, Camerini T, et al. Can fenretinide protect women against ovarian cancer ? J Natl Cancer Inst 1995; 87: 146–7

    Article  PubMed  Google Scholar 

  47. Piantadosi S. Vitamin A analogue for breast cancer prevention: a grade of F or incomplete? [editorial]. J Natl Cancer Inst 1999; 91: 1794–5

    Article  PubMed  CAS  Google Scholar 

  48. Torrisi R, Pensa F, Orengo MA, et al. The synthetic retinoid fenretinide lowers plasma insulin-like growth factor-I levels in breast cancer patients. Cancer Res 1993; 53: 4769–71

    PubMed  CAS  Google Scholar 

  49. Torrisi R, Parodi S, Pensa F, et al. Effect of fenretinide on plasma IGF-I and IGFBP-3 in early breast cancer patients. Int J Cancer 1998; 76: 787–90

    Article  PubMed  CAS  Google Scholar 

  50. Favoni RE, de Cupis A, Bruno S, et al. Modulation of the insulin-like growth factor-I system by N-(4-hydroxyphenyl) retinamide in human breast cancer cell lines. Br J Cancer 1998; 77: 2138–47

    Article  PubMed  CAS  Google Scholar 

  51. Hankinson SE, Willett WC, Colditz GA, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998; 351: 1393–6

    Article  PubMed  CAS  Google Scholar 

  52. Budd TG, Adamson PC, Gupta M, et al. Phase I/II trial of alltrans retinoic acid and tamoxifen in patients with advanced breast cancer. Clin Cancer Res 1998; 4: 635–42

    PubMed  CAS  Google Scholar 

  53. Camerini T, Mariani L, De Palo G, et al. Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 2001; 19: 1664–70

    PubMed  CAS  Google Scholar 

  54. Decensi A, Torrisi R, Bruno S, et al. Randomized trial of fenretinide in superficial bladder cancer using DNA flow cytometry as an intermediate endpoint. Cancer Epidemiol Biomarker Prevent. In press

  55. Conley B, O’Shaughnessy J, Prindville S, et al. Pilot trial of the safety and tolerability, and retinoid levels of N-(4-hydroxyphenyl)retinamide in combination with tamoxifen in patients at high risk of developing invasive breast cancer. J Clin Oncol 2000 Jan; 18(2): 275–83

    PubMed  CAS  Google Scholar 

  56. Mariani L, Formelli F, De Palo G, et al. Chemoprevention of breast cancer with fenretinide (4-HPR): study of long-term visual and ophthalmologic tolerability. Tumori 1996, 82: 444–9

    PubMed  CAS  Google Scholar 

  57. Decensi A, Torrisi R, Polizzi A, et al. Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface. J Natl Cancer Inst 1994; 86: 105–10

    Article  PubMed  CAS  Google Scholar 

  58. Caruso RC, Zujewski J, Iwata F, et al. Effects of fenretinide (4-HPR) on dark adaptation. Arch Ophthalmol 1998; 116: 759–63

    PubMed  CAS  Google Scholar 

  59. Anzano MA, Peer CW, Smith JM, et al. Chemoprevention of mammary carcinogensis in the rat: combined use of raloxifene and 9-cis retinoic acid. J Natl Cancer Inst 1996; 88: 123–5

    Article  PubMed  CAS  Google Scholar 

  60. Ratko TA, Detrisac CJ, Dinger NM, et al. Chemopreventive efficacy of combined retinoid and tamoxifen treatment following surgical excision of a primary mammary cancer in female rats. Cancer Res 1989; 49: 4472–6

    PubMed  CAS  Google Scholar 

  61. Cobleigh MA, Gray R, Graham M, et al. Fenretinide (FEN) versus placebo in postmenopausal breast cancer patients receiving adjuvant tamoxifen (TAM), an Eastern Cooperative Oncology Group Phase III Intergroup Trial (EB193, INT-0151)[abstract]. Proc ASCO 2000; 19: 328A

    Google Scholar 

  62. Costantino JP, Gail MH, Pee D, et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 1999; 91: 1541–8

    Article  PubMed  CAS  Google Scholar 

  63. Bonanni B, Ramazzotto F, Franchi D, et al. A randomised trial of fenretinide in HRT users using IGF-1 as a surrogate biomarker [abstract]. Proceedings of the 2000 San Antonio Breast Cancer Symposium. Breast Cancer Res Treat 2000; 64: A152

    Google Scholar 

Download references

Acknowledgements

The Chemoprotective Unit of the European Institute of Oncology is partially supported by a grant from the Italian Foundation of Cancer Research (FIRC).

Author information

Authors and Affiliations

  1. Chemoprevention Unit, European Institute of Oncology, via Ripamonti 435, 20141, Milan, Italy

    Rosalba Torrisi &  Andrea Decensi

  2. Chemoprevention Unit, National Tumour Institute, Milan, Italy

    Franca Formelli

  3. Department of Clinical Prevention, National Tumour Institute, Milan, Italy

    Tiziana Camerini & Giuseppe De Palo

Authors
  1. Rosalba Torrisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Decensi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Franca Formelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tiziana Camerini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giuseppe De Palo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea Decensi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Torrisi, R., Decensi, A., Formelli, F. et al. Chemoprevention of Breast Cancer with Fenretinide. Drugs 61, 909–918 (2001). https://doi.org/10.2165/00003495-200161070-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200161070-00002

Keywords

Search

Navigation