Home: Educational Supplement: Appendix

Who Should Not Get Tamoxifen?

C. Kent Osborne, M.D.

Tamoxifen is a selective estrogen receptor modulator (SERM) that demonstrates antiestrogenic effects in breast cancer cells and in vaginal mucosa, and estrogenic effects in bone, endometrium, and the liver. These dual effects suggest that women taking tamoxifen might benefit from the drug’s inhibitory effects on the cancer as well as from its agonist effects to maintain bone density and to lower cholesterol. Adverse effects would be expected from the estrogen-like stimulation of the endometrium.

Clinical trials of tamoxifen were started more than 25 years ago. The drug has an established role in the treatment of estrogen receptor (ER)-positive metastatic breast cancer and in adjuvant therapy in patients with primary breast cancer, and an evolving role in treating ductal carcinoma in situ (DCIS) and in prevention of breast cancer.

Invasive Breast Cancer and Tamoxifen

Individual randomized clinical trials as well as meta-analysis of all adjuvant trials clearly demonstrate that 5 years of adjuvant tamoxifen reduces the risk of recurrence and reduces mortality of women with ER-positive early breast cancer (see table 1).

Reductions in recurrence and mortality are seen irrespective of age, with patients under 40 years of age benefiting as much as older patients so long as the tumor expresses ER. Overall, such patients have a 40 to 50 percent annual reduction in the odds of recurrence. Patients whose tumors are strongly ER-positive have a 60 percent proportional reduction in recurrence. In addition, there is a 50 percent reduction in the incidence of contralateral breast cancer in patients treated with adjuvant tamoxifen.

Despite the effects of tamoxifen on cholesterol, no reduction in cardiac mortality has been observed in meta-analysis of tamoxifen adjuvant trials. An increased incidence of well-differentiated endometrial cancer as a result of tamoxifen therapy has been documented, although the beneficial effects of tamoxifen on breast cancer far outweigh that adverse event. An important question is whether patients with ER-negative tumors receive some benefit with tamoxifen adjuvant therapy, either in terms of reducing the risk of recurrence and death from their primary tumor or in terms of the ancillary benefits in relation to contralateral breast cancer, cholesterol, and bone density. The meta-analysis shows no recurrence or mortality benefit in patients whose tumors are ER-negative in either the presence or absence of chemotherapy (EBCTCG, 1998). Two recently reported but as yet unpublished adjuvant trials were prospectively designed to determine the benefits of tamoxifen in ER-negative patients. Intergroup trial 0102 randomized high-risk node-negative patients, both ER-positive and ER-negative, to chemotherapy alone (CMF or CAF) or chemotherapy plus 5 years of tamoxifen (Hutchins, Green, Ravdin, et al., 1998). That trial showed no overall benefit with tamoxifen in the ER-negative subset, with a trend toward an unfavorable outcome in the premenopausal group. Patients with ER-positive tumors received significant benefit.

The other study, NSABP B23, randomized ER-negative patients to chemotherapy alone or chemotherapy plus tamoxifen (Fisher, Anderson, Wolmark, et al., 2000). That trial also showed no benefit from the addition of tamoxifen.

Thus, neither the meta-analysis of all trials nor the two large randomized clinical trials prospectively designed to answer the question show a recurrence or survival benefit for adjuvant tamoxifen in the ER-negative subset. Nonetheless, many physicians prescribe tamoxifen for ER-negative patients because of its potential benefit in reducing contralateral breast cancer. Emerging data that will be presented at this conference, however, suggest that, in marked contrast to the R-positive subset, the incidence of contralateral breast cancer is not reduced by tamoxifen in patients with ER-negative primary tumors. Thus, on the basis of current data, there is no justification for the use of adjuvant tamoxifen in patients whose tumors are ER-negative.

Ductal Carcinoma In Situ (DCIS)

Trials are in progress evaluating the role of tamoxifen in patients with DCIS following mastectomy or breast conservation surgery. Trials on invasive breast cancer suggest that tamoxifen may reduce the risk of ipsalateral breast cancer recurrence in patients treated with breast preservation as well as reduce the incidence of contralateral breast cancer. Such patients have little risk of dying of distant recurrence from their initial breast cancer, and the use of tamoxifen in these patients might be viewed as chemoprevention, much like its use in patients with increased breast cancer risk. One large randomized trial (NSABP B-24) has been completed, and early results have been published (Fisher, Dignam, Wolmark, et al., 2000). More than 1,800 women with DCIS with either positive or negative surgical margins were randomized to lumpectomy plus radiation or to lumpectomy plus radiation plus tamoxifen. Women in the tamoxifen arm had significantly fewer invasive and noninvasive breast cancers in the ipsalateral breast and also a reduction in contralateral breast cancer. Slightly more patients on tamoxifen developed venous thrombotic events, but there have been no treatment-related deaths. As expected, there was an increased rate of endometrial cancer in patients treated with tamoxifen. These data suggest that tamoxifen treatment can be considered in women treated with lumpectomy and radiation therapy to prevent both ipsalateral and contralateral invasive breast cancer. Tamoxifen would also be expected to reduce the incidence of contralateral breast cancer in patients treated by mastectomy, but the drug has not been studied definitively in this group. The role of ER status in predicting tamoxifen benefit in patients with DCIS has not been examined.

Prevention

Three randomized trials have addressed the role of tamoxifen in breast cancer prevention. One of these, the P-1 trial run by the NSABP and reported by Fisher and colleagues (Fisher, Costantino, Wickerham, et al., 1998) was a large double-blind randomized trial involving more than 13,000 women with an increased breast cancer risk receiving either placebo or tamoxifen for 5 years. That trial showed a 50 percent reduction in the incidence of breast cancer after 3 to 4 years of followup. There was also a reduction in bone fractures, but no change in cardiac mortality. The incidence of endometrial cancer increased, as expected, but thus far there are no deaths from endometrial cancer in patients in the tamoxifen arm. A slight increase in the need for cataract surgery in women with preexisting cataracts and a slight increase in thromboembolic events were also reported. Similar data were observed in a trial using raloxifene for osteoporosis (Cummings, Eckert, Krueger, et al., 1999). However, the reduction in breast cancer incidence observed in the latter trial is considered less definitive, since it was a secondary endpoint. Nevertheless, data from that trial add weight to the evidence that SERM therapy reduces the incidence of breast cancer in women who do not yet manifest the disease.

Two other trials using tamoxifen in prevention have been reported (Powles, Eeles, Ashley, et al., 1998; Veronesi, Maisonneuve, Costa, et al., 1998). The trial by Powles and colleagues was a feasibility study randomizing more than 2,000 women who had an increased risk of breast cancer based on family history. Overall, the trial showed no significant reduction in breast cancer incidence, although there was a reduction in the number of ER-positive breast cancers. Interpretation of the evidence from that trial, however, suffers because of the concomitant use of estrogen replacement therapy in many of the women and by its smaller size and initial design as a pilot feasibility trial. The study by Veronesi and colleagues involved 5,000 women who had previously undergone hysterectomy. It showed no overall benefit for tamoxifen, although there was a trend toward reduction in ER-positive breast cancers. Interpretation of the data from that trial is also clouded by the use of hormone replacement therapy by some patients and from a high patient dropout rate.

The cumulative evidence at this time suggests that in high-risk women, 5 years of tamoxifen reduces the incidence of in situ and invasive breast cancer in both pre- and postmenopausal women. A risk-benefit analysis suggests that greater relative benefit will be observed in younger women (Gail, Costantine, Bryant, et al., 1999). Although many questions remain to be answered, tamoxifen can be considered for women meeting the criteria of eligibility for the P-1 trial (Chlebowski, Collyar, Somerfield, et al., 1999). Women not meeting those criteria should not receive tamoxifen until the data clearly demonstrate a favorable risk-benefit ratio.

Conclusion and Future Direction

There are no data to support the use of tamoxifen in patients with ER-negative invasive breast cancer. Tamoxifen can be considered in certain subsets of women with DCIS and in women at increased risk for breast cancer. Women with an average risk for developing breast cancer should not receive tamoxifen at this time. Future studies should address the optimal duration of tamoxifen for treatment and prevention, the value of ER expression in predicting the tamoxifen benefit for patients with ductal carcinoma in situ, the risk-benefit profile obtained by longer followup of patients in prevention trials, health economic outcomes, the role of tamoxifen in tumor prevention in women with hereditary susceptibility to cancer, and trials of other SERMs with a more favorable therapeutic ratio.

References

Chlebowski RT, Collyar DE, Somerfield MR, Pfister DG. American Society of Clinical Oncology technology assessment on breast cancer risk reduction strategies: tamoxifen and raloxifene. J Clin Oncol 1999;17:1939-55. Abstract.

Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA 1999;281:2189-97. Abstract.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451-67. Abstract.

Fisher B, Anderson S, Wolmark N, Tan-Chiu E. Chemotherapy with or without tamoxifen for patients with ER-negative breast cancer and negative nodes: results from NSABP B23. [abstract]. Proc Am Soc Clin Oncol 2000;19:72a. Abstract.

Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for the prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371. Abstract.

Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993-2000. Abstract.

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.

Hutchins L, Green S, Ravdin P, et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of intergroup trial INT 0102. [abstract]. Proc Am Soc Clin Oncol 1998;17:1a. Abstract.

Powles TJ, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998;352:98-101. Abstract.

Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Lancet 1998;352:93-7. Abstract.