We showed that tamoxifen treatment appeared to shorten the time to diagnosis of ER-negative breast cancer by approximately 1 year but was not associated with the time to diagnosis of ER-positive breast cancer. The earlier diagnosis of ER-negative breast cancer might have been a result of more diagnosable tumors or of faster- growing tumors associated with the use of tamoxifen. However, if tamoxifen had stimulated the growth of ER-negative tumors, we would have expected statistically significantly more ER-negative tumors to have been diagnosed during follow-up or at younger ages at diagnosis in the tamoxifen arm than in the placebo arm. We did not observe either of these events among women with ER-negative tumors. The estimated incidences of ER-negative breast cancer (7.4 per 1000 vs 7 per 1000 women) and the median ages at diagnosis (53.5 vs 52.7 years) were about the same in both the tamoxifen and placebo arms, respectively. The observation that more smaller-sized ER-negative tumors were diagnosed among women in the tamoxifen arm than in the placebo arm tends to support the interpretation that earlier diagnosis is a result of more “diagnosable” ER-negative tumors. The relative detection rate by mammography also confirmed that ER-negative tumors were more likely to be detected by mammography than by clinical breast examination in the tamoxifen arm than in the placebo arm, albeit not statistically significantly so. In contrast, no differences were found in the mammography detection rates of ER-positive tumors by treatment arm. Our analysis also showed that chemoprevention with tamoxifen, compared with placebo, reduced the number of invasive ER-positive breast cancers among participants in NSABP's BCPT and also concurred with previous findings that tamoxifen did not reduce the risk of ER-negative invasive breast cancer (1
Because breast cancer is estrogen dependent, the biological function of endocrine therapies on the disease differs according to the ER status of the tumor. It is thus not surprising that the effects of tamoxifen on the reduction of disease incidence and mortality differed by the ER status of the tumor. Our study results also provide information on the effect of tamoxifen treatment on disease surveillance, which could be used to improve the early detection of breast cancer. Some studies (14
) have hypothesized that ER-negative tumors are less likely to be detected by mammography than ER-positive tumors. In this study, we found a similar, although not statistically significant, pattern in the placebo arm: mammography detected 77.4% of ER-negative tumors and 84.1% of ER-positive tumors. Conversely, in the tamoxifen arm, mammography detected 94.7% of ER-negative tumors and 85.7% of the ER-positive tumors. Clearly, the mammography detection rate of ER-positive tumors was changed little by tamoxifen use, but the mammography detection rate of ER-negative tumors increased with tamoxifen use. Our multivariable logistic regression model also indicated that ER-negative breast cancers were more likely to be detected by mammography in the tamoxifen arm than in the placebo arm (OR = 4.68, 95% CI = 0.86 to 25.32, P
= .073), although the difference did not reach statistical significance. These data appear to support the hypothesis that there are differences in mammographic detection of ER-negative breast cancer, but not for ER-positive breast cancer, by treatment group.
Our finding that tamoxifen treatment decreased the time to diagnosis of ER-negative breast cancers is supported by the findings that changes in breast density are associated with the use of tamoxifen (16
) and that breast density appears to be a major factor influencing the sensitivity of mammography screening examinations (19
). Tamoxifen treatment changes the density of normal breast tissue and thereby modifies the contrast between normal tissue and tumor tissue, which would increase the ability of mammography to detect tumors (5
). Unfortunately, these studies (16
) were not stratified by the ER status of the tumor and the BCPT trial did not collect data on breast density. It is therefore unclear why the potential change in breast density did not make a difference in the mammographic diagnosis of ER-positive breast cancer in the tamoxifen arm. One possibility is that tamoxifen treatment increases the contrast between normal tissue and ER-negative tumor tissue more than the contrast between normal tissue and ER-positive tumor tissue. An alternative explanation is that, as an antiestrogen agent, tamoxifen not only modifies breast density but also inhibits the growth of ER-positive breast cancers but not ER-negative breast cancers (22
). The latter explanation somewhat supports the observations of Cuzick et al. (5
) that the change in breast density associated with tamoxifen treatment predicted approximately one-third of the reduction in the incidence of breast cancer that was observed in the prevention trials and that the reduction of incidence occurred only in ER-positive tumors. If the earlier diagnosis of ER-negative breast cancer is a result of the reduction in breast density associated with the use of tamoxifen, then tamoxifen may not have a direct clinical benefit in the reduction of ER-negative breast cancer, even though breast density is an independent risk factor for breast cancer (23
Our study has several limitations. Our analysis was limited by a lack of measurement of breast density either before or after treatment in the BCPT. In addition to its role as an important risk factor in predicting the occurrence of breast cancer, breast density also affects mammography sensitivity at diagnosis of breast cancer. Therefore, information of breast density should be collected at periodic screening examinations in future prevention trials. Another limitation to this study is that the number of ER-negative breast cancers diagnosed was moderately small (a total of 69 women with ER-negative tumors), and thus, any conclusions that are based on these data should be interpreted with caution.
The BCPT was the largest placebo-controlled chemoprevention trial to evaluate tamoxifen as a chemopreventive agent. We used BCPT data to investigate the effect of tamoxifen treatment in primary prevention and early detection settings by the ER status of the tumor. Findings from this study have the potential to increase our knowledge of tamoxifen's effects on the natural history of breast cancer, its primary prevention, and its early detection. The biologic mechanisms associated with the decreased time to diagnosis of ER-negative breast tumors in the tamoxifen arm, compared with that in the placebo arm, remain to be further investigated in treatment and prevention studies.