ADJUVANT TAMOXIFEN THERAPY FOR EARLY-STAGE BREAST-CANCER AND 2ND PRIMARY MALIGNANCIES

Tamoxifen is being increasingly used for the treatment of breast cance r and is undergoing study for the primary prevention of breast cancer. However, concerns have been raised that the drug may increase the inc idence of new primary malignancies, such as endometrial, liver, and co lorectal cancers. Purpose: Our goal was to assess the carcinogenic ris ks associated with long-term use of tamoxifen in women with early stag e breast cancer. Methods: The incidence of new primary cancers among 2 729 women participants of the Stockholm Trial was determined at a medi an follow-up of 9 years. In this trial, after primary surgery, postmen opausal patients aged less than 71 years with unilateral invasive brea st cancer were randomly allocated to receive either 2 years of adjuvan t tamoxifen (40 mg daily) or no adjuvant endocrine therapy. Informatio n on second cancers was obtained by retrospective linkage to the Swedi sh Cancer Registry. To increase statistical power, a joint analysis of the incidence of endometrial and gastrointestinal cancers was perform ed in the following three major studies in Scandinavia evaluating adju vant tamoxifen therapy: the Stockholm Trial, the Danish Breast Cancer Group Trial, and the South-Swedish Trial. These studies included a tot al of 4914 patients with a median follow-up of 8-9 years. All P values were calculated from two-tailed tests of statistical significance. Re sults: 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, th ere was a nearly sixfold increase in endometrial cancers (P < .001) an d a threefold increase in gastrointestinal cancers in the tamoxifen-tr eated patients. The results of the joint studies showed a statisticall y significant increase in endometrial cancers among the tamoxifen-trea ted patients (relative risk [RR] = 4.1; 95% confidence interval [CI] = 1.9-8.9). There was also an excess of gastrointestinal cancers associ ated 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 gastroi ntestinal cancer (e.g., liver cancer) among the tamoxifen-treated pati ents. Conclusion: The endometrium and gastrointestinal organs may be t arget sites for tamoxifen-induced carcinogenesis in humans. Implicatio ns: The increased incidence of colorectal and stomach cancers reported here should be regarded as tentative until supported by long-term dat a from a larger number of tamoxifen trials. Also, appropriate surveill ance of cancer incidence is warranted for the protection of participan ts enrolled in current tamoxifen chemoprevention trials.