Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study.
BACKGROUND
Initial findings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor-positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical significance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial findings.


METHODS
Women (n = 13,388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). Estimates of the net benefit from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided.


RESULTS
After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically significant. The net benefit achieved with tamoxifen varied according to age, race, and level of breast cancer risk.


CONCLUSIONS
Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer. Readily identifiable subsets of individuals comprising 2.5 million women could derive a net benefit from the drug.
Fisher
Bernard
B
Operations Center, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, USA. fisherb2@upmc.edu
Costantino
Joseph P
JP
Wickerham
D Lawrence
DL
Cecchini
Reena S
RS
Cronin
Walter M
WM
Robidoux
Andre
A
Bevers
Therese B
TB
Kavanah
Maureen T
MT
Atkins
James N
JN
Margolese
Richard G
RG
Runowicz
Carolyn D
CD
James
Joan M
JM
Ford
Leslie G
LG
Wolmark
Norman
N
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use*; D015982:Bias; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000517:prevention & control*; D016001:Confidence Intervals; D016889:Endometrial Neoplasms / Q000139:chemically induced; D020847:Estrogen Receptor Modulators / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D050723:Fractures, Bone / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D016017:Odds Ratio; D010024:Osteoporosis / Q000150:complications; D018579:Patient Selection; D011960:Receptors, Estrogen / Q000032:analysis*; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000209:etiology; D013629:Tamoxifen / Q000009:adverse effects / Q000627:therapeutic use*; D013923:Thromboembolism / Q000139:chemically induced / Q000150:complications; D013997:Time Factors
D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D013629:Tamoxifen