Tamoxifen for breast cancer prevention: safety warning
======================================================

* Eric Wooltorton

Reason for posting: Tamoxifen is used as adjuvant hormonal therapy for breast cancer1,2 and may be useful for primary prevention in some women at high risk of the disease (including those with ductal carcinoma in situ [DCIS]).3,4,5 The US Food and Drug Administration recently issued a warning emphasizing that physicians need to advise women that serious and fatal adverse effects, including uterine cancer, stroke and pulmonary embolism,6 have occurred in some women taking the drug for breast cancer prevention.

The drug: Tamoxifen is a nonsteroidal agent with anti-estrogenic properties that is used to treat estrogen-receptor– positive tumours1,2 and DCIS.4 It also has a low affinity for androgen receptors, inhibits prostaglandin synthetase and displays estrogenic-like effects on some body systems, including the bones, endometrium and blood lipids.7 Tamoxifen interacts with coumadin,7 erythromycin, cyclosporin, nifedipine and diltiazem.8 Associated adverse effects include hot flashes, nausea and vomiting, gynecologic changes (e.g., oligomenorrhea, amenorrhea, endometrial hyperplasia, ovarian cysts, fibroids, vaginal dryness or discharge, and pruritus vulvae), bone and tumour pain, hypercalcemia, depression, lightheadedness, headache, alopecia, rash, liver disturbances, cataracts, leukopenia, thrombocytopenia, neutropenia, deep vein thrombosis and pulmonary embolism.7

The Gail model can identify women at high risk of breast cancer (those with a 5-year risk of more than 1.67%)5 so that they can be offered chemoprevention. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial enrolled 13 388 such high-risk women (all over 35 years old) and randomly assigned them to receive either tamoxifen or placebo for 5 years.9 Invasive breast cancer was less common in the tamoxifen group than in the placebo group (3.4 v. 6.8 per 1000 woman-years, relative risk [RR] 0.51, 95% confidence interval 0.39–0.66).9 However, 2 smaller studies — the Italian Tamoxifen Prevention Study (*n* = 5408) and the Royal Marsden Hospital Tamoxifen Randomized Chemoprevention Trial (*n* = 2471) — did not show similar risk reductions (RR 0.92 and 0.94 respectively).3 No trial has yet shown a reduction in breast cancer mortality. Adverse effects identified in these trials included endometrial cancer, deep vein thrombosis, pulmonary emboli and cataracts.3 However, a recent long-term follow-up study (median 6.9 years) of women in the NSABP P-1 trial revealed that the tamoxifen group had an increased rates of uterine sarcoma and stroke as well as endometrial adenocarcinoma and pulmonary embolism (Table 1).6,8

View this table:
[Table1](http://www.cmaj.ca/content/167/4/378/T1)

Table 1. 

What to do: Although the Gail model has not been validated for routine screening, it may allow a preliminary estimate of baseline breast cancer risk (an online risk assessment tool is available at bcra.nci.nih.gov/brc).

Tamoxifen is not appropriate for breast cancer prevention in women at low risk of the disease (5-year risk less than 1.66%),3 and discussions about modifiable risk factors, including dietary fat and alcohol intake,10 physical inactivity,11 breast-feeding12 and post-menopausal hormone replacement exposure13 may be appropriate. Women at higher risk (especially those with a 5-year risk of more than 5%3) who consent to treatment after appropriate appraisal of its risks and benefits may be considered for chemoprevention,3 recognizing the limitations of the evidence (studies have excluded women with thrombophilia) and the fact that tamoxifen is not licensed in Canada for this indication. Many women offered tamoxifen for chemoprevention will decline treatment, often because of a fear of side effects.14 The role, safety and efficacy of raloxifene, an agent with a risk of deep vein thrombosis similar to that of tamoxifen but no apparent effect on the endometrium, is currently under investigation as an alternative chemopreventative agent.15

**Eric Wooltorton** *CMAJ*

## References

1.  1. Levine M. Clinical practice guidelines for the care and treatment of breast cancer: adjuvant systemic therapy for node-positive breast cancer (summary of the 2001 update). CMAJ 2001;164: 644-6.
    
    [FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czo5OiIxNjQvNS82NDQiO3M6NDoiYXRvbSI7czoyMDoiL2NtYWovMTY3LzQvMzc4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

2.  2. Levine M. Clinical practice guidelines for the care and treatment of breast cancer: adjuvant systemic therapy for node-negative breast cancer (summary of the 2001 update). CMAJ 2001;164:213.
    
    [FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czo5OiIxNjQvMi8yMTMiO3M6NDoiYXRvbSI7czoyMDoiL2NtYWovMTY3LzQvMzc4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

3.  3. Levine M, Moutquin JM, Walton R, Feightner J. Chemoprevention of breast cancer. CMAJ 2001;164:1681-90.
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czoxMToiMTY0LzEyLzE2ODEiO3M6NDoiYXRvbSI7czoyMDoiL2NtYWovMTY3LzQvMzc4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

4.  4. Olivotto I, Levine M. Clinical practice guidelines for the care and treatment of breast cancer: the management of ductal carcinoma in situ (summary of the 2001 update). CMAJ 2001;165:912-3.
    
    [FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czo5OiIxNjUvNy85MTIiO3M6NDoiYXRvbSI7czoyMDoiL2NtYWovMTY3LzQvMzc4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

5.  5. Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91:1829-46.
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5jaSI7czo1OiJyZXNpZCI7czoxMDoiOTEvMjEvMTgyOSI7czo0OiJhdG9tIjtzOjIwOiIvY21hai8xNjcvNC8zNzguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

6.  6. Nolvadex [tamoxifen citrate]. In: Medwatch 2002 Safety Information Summaries. Washington: US Food and Drug Administration; 2002 May 15. Available: [www.fda.gov/medwatch/SAFETY/2002/safety02.htm#nolvad](http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#nolvad) (accessed 2002 July 22).
    
    

7.  7. Nolvadex (tamoxifen citrate). In: *Compendium of pharmaceuticals and specialties*. Ottawa: Canadian Pharmacists Association; 2002.
    
    

8.  8. *Nolvadex: tamoxifen citrate* [product monograph]. Wilmington (DE): AstraZeneca Pharmaceuticals; 2002. Available (pdf format): [www.fda.gov/cder/foi/label/2002/17970s37s44s49lbl.pdf](http://www.fda.gov/cder/foi/label/2002/17970s37s44s49lbl.pdf) (accessed 2002 July 22).
    
    

9.  9. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, 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; 90: 1371-88.
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5jaSI7czo1OiJyZXNpZCI7czoxMDoiOTAvMTgvMTM3MSI7czo0OiJhdG9tIjtzOjIwOiIvY21hai8xNjcvNC8zNzguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

10. 10. Laboratory Centre for Disease Control. Breast cancer in Canada. Can Fam Physician 1999;45:1937-9.
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=10463094&link_type=MED&atom=%2Fcmaj%2F167%2F4%2F378.atom) 

11. 11. Katzmarzyk PT, Gledhill N, Shephard RJ. The economic burden of physical inactivity in Canada. CMAJ 2000;163(11):1435-40.
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czoxMToiMTYzLzExLzE0MzUiO3M6NDoiYXRvbSI7czoyMDoiL2NtYWovMTY3LzQvMzc4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

12. 12. Beral V. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet 2002;360:187-95.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0140-6736(02)09454-0&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=12133652&link_type=MED&atom=%2Fcmaj%2F167%2F4%2F378.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000176988500007&link_type=ISI) 

13. 13. Chen CL, Weiss NS, Newcomb P, Barlow W, White E. Hormone replacement therapy in relation to breast cancer. JAMA 2002;287(6):734-41.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1001/jama.287.6.734&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11851540&link_type=MED&atom=%2Fcmaj%2F167%2F4%2F378.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000173809500030&link_type=ISI) 

14. 14. Port ER, Montgomery LL, Heerdt AS, Borgen PI. Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol 2001;8:580-5.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1007/s10434-001-0580-9&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=11508619&link_type=MED&atom=%2Fcmaj%2F167%2F4%2F378.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000170243700005&link_type=ISI) 

15. 15. Lorraine J. Raloxifene and breast cancer [letter]. CMAJ 2001;165(7):888.
    
    [FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czo5OiIxNjUvNy84ODgiO3M6NDoiYXRvbSI7czoyMDoiL2NtYWovMTY3LzQvMzc4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==)