NSABP P-1 Breast Cancer Prevention Trial (tamoxifen)

Before 1998, tamoxifen was a treatment for breast cancer, not a way to prevent it. Women at high risk, because of age, a prior lobular carcinoma in situ or atypical biopsy, or a high Gail model score, had no drug proven to lower that risk. The idea came from adjuvant trials in which women given tamoxifen developed fewer cancers in the opposite breast, and in 1992 the National Surgical Adjuvant Breast and Bowel Project, whose report was led by Bernard Fisher, began the P-1 trial.

The NSABP P-1 trial randomized 13,388 women aged 60 or older, aged 35 to 59 with a five-year Gail risk of at least 1.66 percent, or with lobular carcinoma in situ, to tamoxifen 20 mg daily or placebo for five years. The trial was unblinded early because of the positive results; through 69 months invasive breast cancer occurred at 22.0 per 1,000 women on tamoxifen against 43.4 on placebo, a 49% reduction. The FDA approved tamoxifen for risk reduction in high-risk women on October 29, 1998.

The benefit was not distributed evenly across tumor biology. The reduction held in every age group, from 44 percent in women 49 or younger to 55 percent in those 60 or older, and noninvasive breast cancer fell by half. Estrogen receptor-positive tumors fell by 69 percent, while ER-negative cancers were unaffected, as tamoxifen's mechanism would predict. On the other side of the ledger, tamoxifen increased rates of endometrial cancer, stroke, deep venous thrombosis and pulmonary embolism, mainly in women aged 50 or older. All the endometrial cancers on tamoxifen were stage I, and hip, wrist and spine fractures became less common.

The NSABP's next prevention trial, STAR, began in 1999 and compared tamoxifen with raloxifene in 19,747 postmenopausal women; the two drugs prevented invasive breast cancer equally well (163 against 168 cases). The aromatase inhibitors then showed the same effect in high-risk postmenopausal women: exemestane in the MAP.3 trial (2011) and anastrozole in IBIS-II (2014), where breast cancer occurred in 2 percent against 4 percent on placebo.

Victor Vogel of the University of Pittsburgh was first author of the 2006 STAR report, which also counted 36 uterine cancers on tamoxifen against 23 on raloxifene. Uptake of tamoxifen for prevention stayed low; the MAP.3 investigators wrote in 2011 that tamoxifen and raloxifene had limited patient acceptance. After seven years of follow-up, invasive breast cancer in P-1 was still 43 percent lower with tamoxifen, 24.8 against 42.5 cases per 1,000 women.