TAMOXIFEN FOR PREVENTION OF BREAST-CANCER - REPORT OF THE ATIONAL-SURGICAL-ADJUVANT-BREAST-AND-BOWEL-PROJECT P-1 STUDY

Background: The finding of a decrease in contralateral breast cancer i ncidence following tamoxifen administration for adjuvant therapy led t o the concept that the drug might play a role in breast cancer prevent ion. To test this hypothesis, the National Surgical Adjuvant Breast an d Bowel Project initiated the Breast Cancer Prevention Trial (P-l) in 1992. Methods: Women (N = 13388) at increased risk for breast cancer b ecause they 1) were 60 years of age or older, 2) were 35-59 years of a ge with a 5-year predicted risk for breast cancer of at least 1.66%, o r 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n = 6707) or 20 mg/day tamoxifen (n = 6681) for 5 years. Call's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the pro bability (risk) of occurrence of breast cancer over time. Results: Tam oxifen reduced the risk of invasive breast cancer by 49% (two-sided P< .00001), with cumulative incidence through 69 months of follow-up of 4 3.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, re spectively. The decreased risk occurred in women aged 49 years or youn ger (44%), 50-59 years (51%), and 60 years or older (55%); risk was al so reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predic ted 5-year risk. Tamoxifen reduced the risk of noninvasive breast canc er by 50% (two-sided P<.002), Tamoxifen reduced the occurrence of estr ogen receptor-positive tumors by 69%, hut no difference in the occurre nce of estrogen receptor-negative tumors was seen. Tamoxifen administr ation did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures wa s observed. The rate of endometrial cancer was increased in the tamoxi fen group (risk ratio = 2.53; 95% confidence interval = 1.35-4.97); th is increased risk occurred predominantly in women aged 50 years or old er. All endometrial cancers in the tamoxifen group were stage I(locali zed disease); no endometrial cancer deaths have occurred in this group . No liver cancers or increase in colon, rectal, ovarian, or other tum ors was observed in the tamoxifen group. The rates of stroke, pulmonar y embolism, and deep-vein thrombosis were elevated in the tamoxifen gr oup; these events occurred more frequently in women aged 50 years or o lder. Conclusions: Tamoxifen decreases the incidence of invasive and n oninvasive breast cancer. Despite side effects resulting from administ ration of tamoxifen, its use as a breast cancer preventive agent is ap propriate in many women at increased risk for the disease.