APPENDIX I: BREAST CANCER PREVENTION: TAMOXIFEN AND DIETARY CONSIDERATIONS

Avi Barbasch, MD

As of this writing, there is no evidence that BRCA1 or BRCA2 positive patients can prevent the development of breast cancer by the ingestion of tamoxifen or by dietary intervention. Reviews of breast cancer treatment have shown that the incidence of a subsequent contralateral breast cancer is reduced by 39% when tamoxifen therapy is administered.¹ The evidence that contralateral breast cancer may be reduced by the use of this therapy has led to the initiation of three prospectively randomized trials of prevention of initial breast cancer in the United Kingdom, United States and Italy respectively.² The US trial, NSABP P-1, has recently closed, and preliminary results suggest a 45% reduction in breast cancer incidence among high-risk participants who took tamoxifen. However, definitive recommendations will need to await final publication of the study data.

While the conclusive data supporting the value of tamoxifen as a preventive agent are being gathered, the toxicity of tamoxifen is of great concern. Several studies have linked tamoxifen administration to the development of proliferative and neoplastic changes in the endometrium.^3,4,5 While some minimize the carcinogenic potential of tamoxifen on the uterus, it is noteworthy that the Italian prevention trial will only accept women for study who have had a hysterectomy.⁶ Early reports of the US Breast Cancer Prevention Trial revealed that tamoxifen did increase the women's chance of developing endometrial cancer, pulmonary embolism and deep vein thrombrosis.

Recent findings by the Stockholm Breast Cancer Study group suggest that there is a modest increased risk of gastrointestinal cancers (especially colorectal and stomach cancers) in women taking tamoxifen⁷ though no other study has confirmed this observation. The results of other long-term tamoxifen trials may help to confirm or refute this carcinogenic risk.

The possibility of decreasing the toxic effects of tamoxifen with the concomitant administration of retinoic acid has been proposed⁸ and is the subject of ongoing trials. Furthermore, new hormonal agents may prove to be efficacious in preventing breast cancer with little toxic effect on the uterus⁹, though definitive data are lacking.

Other toxic effects of tamoxifen include hot flashes, vaginal discharge, menstrual irregularities¹⁰ and thromboembolic disease¹¹ in approximately 1-2% of patients. Also of concern is the potential for ocular toxicity.¹²

In view of the rare possibility of serious toxicity associated with tamoxifen use, and given the lack of definitive data showing that tamoxifen will prevent the development of breast cancer, no recommendation for the prophylactic use of tamoxifen outside of clinical trials can be made at this time.

Other interventions that may decrease the risk of developing breast cancer are based on case-control studies suggesting a relationship between dietary intake of various micro- and macronutrients and the development of breast cancer.^13,14 To date there have been no prospective, random studies in the United States that confirm the claim that dietary changes will reduce the incidence of breast cancer.¹⁵ It is possible that some of the ongoing prospective dietary trials, including the Women's Health Initiative Dietary Modification Trial, will yield data confirming the value of dietary intervention in preventing breast cancer.

In summary, no recommendation of drug or dietary intervention for the prevention of breast cancer can be made at this time. Several prospective randomized studies, now ongoing, may help to identify such methods of breast cancer prevention in the near future.

References:

1. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet, 339:1 (1992).

2. Jordan VC. An overview of considerations for the testing of tamoxifen as a preventive for breast cancer. Ann NY Acad Sci, 768:141 (1995).

3. Daniel Y, Inbar MD, Bar-Am A. The effects of tamoxifen treatment on the endometrium. Fertil Steril, 65:1083 (1996).

4. Cohen CJ, Roheman J. Endometrial cancer, management of high-risk and recurrence including the tamoxifen controversy. Cancer, 76:2044 (1995).

5. Decensi A, Fontana V, Bruno S, et al. Effect of tamoxifen on endometrial proliferation. J Clin Oncol, 14:434 (1996).

6. Venchieri C. Breast cancer prevention study initiated in Italy. J Nat'l Canc Inst, 84:1555 (1992).

7. Rutquist LE, Johansson H, Signomklao T, et al. for the Stockholm Breast Cancer Study Group: Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Nat'l Canc Inst, 87:645 (1995).

8. Carter CA, Pogribny M, Davidson A, et al. Effects of retinoic acid on cell differentiation and reversion toward normal in human endometrial adenocarcinoma (RL 95-2) cells. Anticancer Res, 16:17 (1996).

9. Jordan VC. Third Annual William L. McGuire Memorial Lecture "Studies on the estrogen receptor in breast cancer" - 20 years as a target for the treatment and prevention of cancer. Breast Canc Res Treat, 36:267 (1995).

10. Jordan VC. Tamoxifen: toxicities and drug resistence during the treatment and prevention of breast cancer. Ann Rev Pharmacol Toxicol, 35:195 (1995).

11. Deshmulsh N, Tripothi SP. Thrombosis of tibiol arteries in a patient receiving tamoxifen therapy. Cancer, 76:1006 (1995).

12. Nayfield SG, Gorin MB. Tamoxifen-associated eye disease: a review. J Clin Oncol, 14:1018 (1996).

13. Franceschi S, Fevero A, Decarli A, et al. Intake of macronutrients and risk of breast cancer. Lancet, 347:1351 (1996).

14. Stoll BA. Can supplementary dietary fiber suppress breast cancer growth? Brit J Cancer, 73:557 (1996).

15. Henderson MM. Nutritional aspects of breast cancer. Cancer, 76:2053 (1995).