Tamoxifen and Breast Cancer Incidence Among Women with Inherited Mutations in BRCA1 and BRCA2
Tamoxifen and Breast Cancer Incidence Among Women with Inherited Mutations in BRCA1 and BRCA2
Abstract & Commentary
The rationale for the present analysis is compelling. King and colleagues hypothesized that tamoxifen would protect against the development of breast cancer only in women prone to breast cancers that express estrogen receptors (ER). They note that current data show that 76% of breast tumors found in women who carry the BRCA2 mutation are ER-positive. In contrast, 83% of breast cancers found in women who carry a BRCA1 mutation are ER-negative. They thus reasoned that tamoxifen use would reduce the likelihood of developing a breast carcinoma in women who carry the BRCA2 mutation but not the BRCA1 mutation.
To test this hypothesis, King et al determined the BRCA mutation status of the 288 women who developed breast cancer while participating in the Breast Cancer Prevention Trial (BCPT). The BCPT was a randomized, double-blind trial conducted from 1992-1998. Tamoxifen was given to 13,388 women older than age 35 who were determined to be at high risk of developing invasive breast cancer. High risk was defined by any one of the following: the Gail model;1 age > 60 years; or lobular carcinoma in situ. Eighty percent of participants were followed for 3 years and 65% for 5 years.
The sample resulted in 320 cases of breast cancer (2.4% of the study group), but BRCA mutation status could only be determined in 288. Of those, only 19 (6.6%) had a BRCA mutation; 11 had BRCA2 and 8 had BRCA1. The BRCA mutation status of the women who did not develop breast cancer is unknown. Of those with BRCA1 mutations who developed breast cancer, 5 received tamoxifen and 3 got placebo. King et al calculated that tamoxifen use was associated in BRCA1 with a relative risk of 1.67 with a confidence interval of 0.32-10.70. Of those with BRCA2 mutations who developed breast cancer, 3 got tamoxifen and 8 received placebo. They calculated a relative risk of 0.38 for tamoxifen use, with a confidence interval of 0.06-1.56 (statistically nonsignificant). (King MC, et al. JAMA. 2001;286:2251-2256.)
Comment by Sarah L. Berga, MD
King et al posed an interesting question that had its genesis in their appreciation of the molecular biology of breast cancer. Unfortunately, the data set they chose to mine was relatively small. While the results do not contradict their hypothesis, they certainly do not prove it either. The most obvious limitation was the paucity of cases that were BRCA-positive. If one ignores the confidence intervals, the relative risks are impressive. But the confidence intervals are wide and include 1.0, so the results are not statistically significant.
There are other limitations to consider in interpreting the study. First, the hypothesis is based on some assumptions that may not be true. King et al state that tamoxifen acts as an anti-estrogen in breast tissue. Would that the world were so clear. There are annoying complexities that get overlooked by that statement, including the fact that there is more than one estrogen receptor subtype in breast tissue and that tamoxifen may be an antagonist for ER-alpha, but an agonist for ER-beta. Also, the main metabolite of tamoxifen is 4-hydroxytamoxifen and it may behave as an estrogen in some tissues. In an in vitro culture system, tamoxifen may act as an inhibitor of cell growth of breast cancer cell lines. However, in an in vitro model, tamoxifen is not metabolized and the interaction between the glandular and stromal elements of breast tissue is removed. Thus, cell culture results may not tell us what happens in vivo. Further, when tamoxifen is given to premenopausal women, it increases FSH concentrations. This in turn drives folliculogenesis and raises estrogen levels. Thus, tamoxifen use may result in a different hormonal milieu in pre- vs. postmenopausal women. The sample size is too small to address this issue. Finally, King et al note that in the whole cohort, tamoxifen use appeared to protect against the development of breast cancer. However, none of the participants has yet been followed for more than 10 years, so it is unclear how long the protective effect lasts (assuming that it is real).
My main reason for reviewing this article is to alert you to the fact that the small sample size precludes firm conclusions. I realize that the hypothesis is compelling. The concept being tested may be true. But the present data do not help us to know if it is. Thus it seems premature to act on these data clinically. It would be nice to know if tamoxifen is likely to protect against the development of breast cancer and, if so, in what populations it is protective. It would also be nice to know the mechanisms underlying its putative protective actions. A recent study by O’Meara and colleagues (which I reviewed in a recent issue of OB/GYN Clinical Alert) found that estrogen use by breast cancer survivors improves survival and reduces recurrences.2,3 For all we presently know, tamoxifen may exert its protective actions by acting as an estrogen rather than an anti-estrogen in vivo at the level of the breast. At present, we really have no clinical guidelines as to who should use tamoxifen as prophylaxis against breast cancer and for how long. The risks and benefits of long-term tamoxifen use are a matter of conjecture, but its extended use is not necessarily benign.
References
1. Gail MH, et al. J Natl Cancer Inst. 1999;91: 1829-1846.
2. O’Meara ES, et al. J Natl Cancer Inst. 2001;93: 754-761.
3. Berga, SL. OB/GYN Clinical Alert. 2001;18(3):17-18.
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