These findings suggest that the use of HT is not associated with an increase in the risk of breast cancer among women with a BRCA1
mutation. We were interested in examining HT use and breast cancer risk in BRCA1
mutation carriers because oophorectomy has become a standard of care in North America and Western Europe for preventing cancer in women with a BRCA1
mutation. Currently, after receiving a positive genetic test result, 68% of women in the United States and 54% of women in Canada with a BRCA1
mutation undergo oophorectomy (12
). The surgery has been associated with risk reductions of 50% or more for breast cancer (4
) and of 80% for ovarian or peritoneal cancer (13
). Some women might be reluctant to undergo premenopausal oophorectomy because of the effects of surgical menopause and are concerned that if HT were taken to alleviate symptoms, then their risk of breast cancer might rise.
We observed an OR below unity, indicative of an inverse association between HT use and breast cancer risk. The magnitude of the association appeared to be as great, or even greater, for women after surgical menopause than it was for women after natural menopause. This information should be reassuring to women who wish to undergo preventive oophorectomy before menopause, but it needs to be confirmed in subsequent studies. Premenopausal women face a greater residual risk of breast cancer than do women who have entered menopause; for them, the net reduction in breast cancer risk associated with oophorectomy is substantial (4
). In the noncarrier population, the increased breast cancer risk associated with HT appears to be stronger for ER-positive cancers than ER-negative cancers (14
). If HT were a risk factor for ER-positive breast cancer in BRCA1
mutation carriers as well, we would have expected that a greater proportion of women with ER-positive breast cancers had used HT than women with ER-negative breast cancers. This was not seen, but because we were able to obtain ER status for only about one-half of the breast cancer patients, the numbers are too small to draw a definite conclusion.
In this study, neither use of estrogen alone nor use of estrogen combined with progesterone was associated with an increase in breast cancer risk among BRCA1
mutation carriers. This observation is in contrast to the situation in the general (ie, noncarrier) population, in which formulations containing both estrogen and progesterone have been associated with a substantial increase in breast cancer risk. For example, in the Women's Health Initiative randomized trial, a hazard ratio (HR) of 1.3 (95% CI = 1.0 to 1.6) was reported for breast cancer in association with use of estrogen plus progesterone (5
), and an HR of 0.8 (95% CI = 0.6 to 1.0) was reported for estrogen alone (7
). In the Million Women Study (15
), an HR of 2.0 (95% CI = 1.9 to 2.1) was associated with current use of estrogen plus progesterone, and an HR of 1.3 (95% CI = 1.2 to 2.4) was associated with current use of estrogen alone.
The increase in breast cancer risk in the Million Women Study was restricted to current HT users; after treatment stopped, the risk dissipated rapidly. A rapid and reversible effect might be seen if HT accelerated the growth of existing ER-positive tumors or preneoplastic lesions. The majority of BRCA1
-associated breast cancers in our study (68%) were ER negative; if the adverse effect of HT were limited to ER-positive cancers, then we would not expect to see an acute effect of similar magnitude in mutation carriers. It may be also that HT use protects against the early stages of cancer development, which results in a decline in the incidence of breast cancer later in life. The Women's Health Initiative randomized trial (5
) measured the combined effect of past and current use of estrogen on breast cancer risk; the OR for estrogen alone was borderline protective (OR = 0.77, 95% CI = 0.59 to 1.01). It has been proposed that the rapid decline in breast cancer risk seen in the United States in 2003 is the consequence of a drop in HT usage in the preceding years (14
). The decline in incidence was most pronounced for ER-positive tumors, favoring the hypothesis that the use of HT is associated with a rapid but reversible increase in the risk of ER-positive breast cancers. If HT promotes the growth of existing ER-positive breast cancers but protects against the early stages of development of new breast cancers (ER positive and ER negative), then we would expect HT to protect against breast cancer in BRCA1
mutation carriers (which are mostly ER negative).
We saw no association between the duration of HT use and the risk of breast cancer among BRCA1
mutation carriers, and the association with past use was similar to that of current use. This observation is consistent with the hypothesis that transient exposure to HT is protective; ie, HT might induce the differentiation of precursor cancer cells and thereby prevent cancer later in life. It is of interest that both tamoxifen and oophorectomy are also effective in reducing the risk of postmenopausal breast cancer in BRCA1
mutation carriers (4
). It may be that estrogens and antiestrogens modify breast cancer risk at different stages of progression. For example, estrogen might act early in carcinogenesis, on stem cells or preneoplastic lesions, and tamoxifen and oophorectomy might act at a later stage, eg, in small established cancers.
Another possible reason for the inverse association we observed between HT and breast cancer risk in BRCA1
mutation carriers is that estrogen increases expression of BRCA1
). In cells that have not undergone loss of homozygosity (ie, that retain one normal BRCA1
allele), this increase could lead to an increased cellular level of the wild-type protein, and thereby promote genetic stability.
There is one previous study of HT in BRCA1
mutation carriers. Rebbeck et al. (9
) examined the association between oophorectomy and breast cancer risk in a historical cohort study of 462 BRCA1
mutation carriers. They found that the OR for breast cancer associated with oophorectomy was 0.40 (95% CI = 0.18 to 0.92) in the entire study group and 0.37 (95% CI = 0.14 to 0.96) in the subgroup of women with oophorectomy who used HT. However, in that study, use of HT was not evaluated independently of menopause because the sample size was small (there were only three women with breast cancer and HT exposure in the study by Rebbeck et al., compared with 47 in the current study).
Other areas of concern with regard to the secondary effects of HT in BRCA1
mutation carriers include possibly elevated risks of endometrial and ovarian cancer. In the general population, estrogen alone is avoided in women with an intact uterus because of the established association between unopposed estrogen and endometrial cancer (17
). In a recent study, we reported that the risk of endometrial cancer was increased in a cohort of carriers of BRCA1
mutations, compared with noncarrier conrol subjects, but the increase was statistically significant only in those with past tamoxifen use (18
). Of the six women with incident endometrial cancer observed in this earlier study, four women had a past history of tamoxifen use, but none had previously taken HT. A recent analysis of the Million Women Study (19
) found an increased risk of 1.2 (95% CI = 1.1 to 1.3) for ovarian cancer in association with HT use. However, in a small study of HT in BRCA1
mutation carriers (20
), we did not see any increase in the risk of ovarian cancer in women with a past use of HT (OR = 0.93, 95% CI = 0.56 to 1.56).
The principal strength of our study is that we restricted our observations to postmenopausal women, that is, women who are candidates for HT. Case patients and control subjects were closely matched for age and age at menopause.
Our study also has limitations. One is the relatively small sample size. From a database containing more than 6000 patients, we studied 236 matched pairs of women with and without breast cancer. The average age at interview of the case patients and control subjects was 58 years. This subgroup represents a small proportion of the overall BRCA1 mutation cohort; however, most women in the database could not contribute to the study, either because they had not yet reached menopause or because they had developed early-onset breast cancer. Women who had preventive mastectomy or who used tamoxifen were also excluded.
There is also the possibility of unmeasured confounders. By matching on age and type of menopause, we excluded the potential for bias that might arise if the age of menopause or type of menopause were correlated with the likelihood of receiving hormones. However, if other (currently unknown) factors correlate with the decision to take HT, these factors could potentially lead to a bias in the results.
Third, the validity of our results depends on the accuracy of the subjects’ recall. The women in the study reported on the type of hormone preparation and the duration of use, but these values were not confirmed by review of medical records. Women who were unsure of the hormone formulation were excluded. We divided exposures by duration of HT but did not classify exposures according to the doses of the constituent hormones. It is also possible that case patients and control subjects differentially reported their history of hormone use, but recall bias would generate a spuriously elevated OR associated with the exposure, whereas we observed an inverse association.
Fourth, we studied prevalent cases; on average, 5.6 years had elapsed between the diagnosis of breast cancer and the completion of the questionnaire. If previous HT use was associated with a decreased survival of breast cancer following a diagnosis of breast cancer, then we may see few HT users among long-time breast cancer survivors, resulting in a spurious negative association.
In conclusion, these data are reassuring in suggesting that HT is probably not contraindicated in women with a BRCA1 mutation. Although the data cannot yet be considered definitive, we observed a statistically significant reduction in the risk of breast cancer following HT use, in both the unadjusted and adjusted analyses. It is important that these findings be replicated. The observed associations were not different for women who used estrogen alone or estrogen plus progesterone. There was little difference in the observed ORs associated with less than 3 years and 3 or more years of exposure, and therefore it is not possible for us to recommend an optimum duration of use. We did not include patients with BRCA2 mutations in this study because the sample size was small. It is important that these data be confirmed in other populations, including in women with BRCA2 mutations. It is also important to evaluate the other risks and benefits associated with HT use in women at high risk for breast cancer.