Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group.

BACKGROUND

Tamoxifen is being increasingly used for the treatment of breast cancer and is undergoing study for the primary prevention of breast cancer. However, concerns have been raised that the drug may increase the incidence of new primary malignancies, such as endometrial, liver, and colorectal cancers.

PURPOSE

Our goal was to assess the carcinogenic risks associated with long-term use of tamoxifen in women with early stage breast cancer.

METHODS

The incidence of new primary cancers among 2729 women participants of the Stockholm Trial was determined at a median follow-up of 9 years. In this trial, after primary surgery, postmenopausal patients aged less than 71 years with unilateral invasive breast cancer were randomly allocated to receive either 2 years of adjuvant tamoxifen (40 mg daily) or no adjuvant endocrine therapy. Information on second cancers was obtained by retrospective linkage to the Swedish Cancer Registry. To increase statistical power, a joint analysis of the incidence of endometrial and gastrointestinal cancers was performed in the following three major studies in Scandinavia evaluating adjuvant tamoxifen therapy: the Stockholm Trial, the Danish Breast Cancer Group Trial, and the South-Swedish Trial. These studies included a total of 4914 patients with a median follow-up of 8-9 years. All P values were calculated from two-tailed tests of statistical significance.

RESULTS

In the Stockholm Trial, there was a statistically significant (P = .008) reduction in the incidence of second primary cancers in the contralateral breast among the tamoxifen-treated patients. However, there was a nearly sixfold increase in endometrial cancers (P < .001) and a threefold increase in gastrointestinal cancers in the tamoxifen-treated patients. The results of the joint studies showed a statistically significant increase in endometrial cancers among the tamoxifen-treated patients (relative risk [RR] = 4.1; 95% confidence interval [CI] = 1.9-8.9). There was also an excess of gastrointestinal cancers associated with tamoxifen. Most of this excess involved colorectal cancers (RR = 1.9; 95% CI = 1.1-3.3) and stomach cancer (RR = 3.2; 95% CI = 0.9-11.7). There was no substantial increase in any other type of gastrointestinal cancer (e.g., liver cancer) among the tamoxifen-treated patients.

CONCLUSION

The endometrium and gastrointestinal organs may be target sites for tamoxifen-induced carcinogenesis in humans.

IMPLICATIONS

The increased incidence of colorectal and stomach cancers reported here should be regarded as tentative until supported by long-term data from a larger number of tamoxifen trials. Also, appropriate surveillance of cancer incidence is warranted for the protection of participants enrolled in current tamoxifen chemoprevention trials.