EDITORIAL

Preventing Hormone-Dependent Breast Cancer in High-Risk Women

Victor G. Vogel, Shelly Lo

Affiliations of authors: V. G. Vogel, S. Lo, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Correspondence to: Victor G. Vogel, M.D., M.H.S., Magee/UPCI Breast Program, University of Pittsburgh School of Medicine, 300 Halket St., Rm. 3524, Pittsburgh, PA 15213–3180 (e-mail: vvogel{at}mail.magee.edu).

Chemoprevention is the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent the progression of premalignant lesions to invasive carcinoma. Four major trials have used tamoxifen, the prototypical selective estrogen receptor modulator (SERM), as a breast cancer chemopreventive agent with differing results. The Royal Marsden trial (1), a pilot study for the International Breast Cancer Intervention Study (IBIS-I) trial (2), and the initial analysis of the Italian tamoxifen prevention study (3) showed no decrease in the incidence of breast cancer among women using tamoxifen. By contrast, both the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study (4) and the IBIS-I trial (2) did show reduction in breast cancer risk with tamoxifen.

In this issue of the Journal, the authors of the Italian study have re-analyzed their data after a median follow-up of 81.2 months (5). By contrast with their two earlier publications (3, 6), their re-analysis shows a reduction in the development of breast cancer in a high-risk population assigned to tamoxifen. These current data update the previous publications that have reported preliminary and essentially identical overall results from this trial. The data provided here are new in their identification of the high-risk cohort.

In the Italian study, 5408 women with hysterectomies were assigned randomly either to tamoxifen (20 mg per day) or placebo for 5 years. At the time of entry, almost half of the women (48.3%) had bilateral oophorectomy, 18.6% had a unilateral oophorectomy, and only 26.3% had conservation of both ovaries. Oophorectomy reduces the risk of developing invasive breast cancer (7), and menopause is associated with an increased likelihood that breast cancer will be estrogen receptor (ER)-positive. This cohort of Italian women, therefore, was at low to normal risk for the development of breast cancer. Initial results published after a median follow-up of 46 months showed no statistically significant difference in breast cancer development between the two groups (3). In that subgroup analysis, there was a statistically significant reduction of breast cancer risk among women in the tamoxifen group who also used hormone replacement therapy (HRT) during the trial. Among 390 women on HRT and assigned to placebo, eight cases of breast cancer were diagnosed. By contrast, among 362 women taking both HRT and tamoxifen, only one case of breast cancer was diagnosed (P = .022).

An update of the results from the trial published in 2002 reported an 81.2-month median follow-up and did not show a statistically significant difference in breast cancer development in women who were at usual or reduced risk (6). Breast cancer was diagnosed in 1.7% of women in the control group compared with 1.3% of women in the tamoxifen group (P = .215). There was a benefit of tamoxifen in those who used HRT where the cumulative incidence of breast cancer was 0.92%. By contrast, the group of women who used HRT and were assigned to the placebo group had a cumulative incidence of breast cancer of 2.58%. Breast cancer was detected in 2% of women who used HRT at any point in the study and who were in the placebo group versus 1% of women HRT users assigned to tamoxifen (P = .022). Because the HRT users were a subgroup not originally defined in the protocol, the results, however, should be interpreted with caution.

The risk of breast cancer is increased by using combined estrogen/progestin HRT for 24 months or longer (8). We are not given information about what hormone preparation(s) were used by women in the Italian trial, but it is likely that they received estrogen alone after hysterectomy. Regardless of the HRT preparations used, the rate of breast cancer development after 81.2 months of follow-up in the Italian trial was 2.58% among HRT users in the placebo group but only 1.59% among the women assigned either to placebo or tamoxifen who had never used HRT (6).

In this issue of the Journal, the data were re-analyzed after stratifying the women into two groups: those who are at increased risk of developing ER-positive tumors (high risk), and those at low risk. Factors that placed a woman in the high-risk group included reproductive and hormonal characteristics (i.e., height >160 cm, age at menarche <13 years, nulliparity, age at first birth after age 24, and no oophorectomy). When the participants were divided into high-risk (702 women, 13% of the study population) or low-risk groups (4693 women, 87% of the study population), tamoxifen had a protective effect on the development of breast cancer among women in the high-risk group (n = 3 versus n = 15 among placebo users, P = .003). The overall risk of breast cancer in the high-risk group increased threefold compared with the overall risk in the low-risk group (hazard ratio [HR] = 3.32, 95% confidence interval [CI] = 1.78 to 6.17). Tamoxifen use decreased the incidence of breast cancer by 82% in the high-risk group but not in the low-risk group (tamoxifen = 31, placebo = 30; P = .89).

These findings can be compared with other published data. The IBIS-I trial, a multinational study, showed a 32% reduction in the risk of developing invasive breast cancer among high-risk women treated with tamoxifen with 50 months median follow-up (2). Participation in that trial required at least a twofold relative risk for breast cancer for women aged 45–70 years, a fourfold relative risk for women aged 40–44 years, and a 10-fold relative risk for women aged 35–39 years. Risk factors used included a combination of family history, lobular carcinoma in situ, atypical hyperplasia, nulliparity, and benign breast biopsies. Similar to the Italian trial, in the IBIS-I study there was a differential effect of tamoxifen based on the status of participants‘ use of HRT (2). Women who used HRT during the trial experienced a 24% reduction in the risk of developing invasive breast cancer with tamoxifen use, similar to the 27% reduction in risk observed among women who had never used HRT; whereas women who had used HRT only before initiating tamoxifen therapy in IBIS-I (and not during the trial) had a statistically significant 57% reduction in their risk of breast cancer.

Like the Italian study, the IBIS-I investigators used a model to predict the absolute 10-year risk of developing breast cancer, but the details of their model have not been published. Approximately half of the Italian women did not have their ovarian function preserved according to their operative reports, but half did. We have no data about either ovarian function in these women or about the status of their endogenous hormones after their surgery and entry into the trial. Serum estradiol levels may predict women who will respond to risk reduction with SERMs (9), and this potential predictive factor should be explored further in future risk reduction trials. Most of the breast cancers among Italian subjects (n = 45) occurred in women whose ovarian function was reported to be preserved, and among these women, tamoxifen reduced risk by 37% (P>.05). If the women in the Italian trial would have continued with active menstrual cycles without hysterectomy, initial concerns about endometrial malignancy were not valid because risk is increased only in postmenopausal women (4).

The risk stratification in the Italian study was retrospective, and all the cautions about post hoc subset analyses apply when interpreting their data. Because of the small number of women in the trial, only two of the subset analyses reached statistical significance for either breast cancer risk or for the effect of tamoxifen on these risk-derived subsets. The reported apparent benefits must be interpreted cautiously because eight retrospective groupings were used, making chance findings likely. The data suggest, however, that for the 751 women who "always" used HRT before and during the trial, their risk of developing breast cancer was doubled (HR = 2.07, 95% CI = 1.02 to 4.19), and tamoxifen reduced that risk by more than 60% (HR = 0.38, 95% CI = 0.10 to 1.44).

Taken together, the data from both the Italian and IBIS-I trials suggest that women who have used or are currently using HRT may be appropriate candidates for breast cancer risk reduction using SERMs. Additional data about this question will be available from the NSABP Study of Tamoxifen And Raloxifene (STAR trial) where 71% of subjects used HRT before entry into the trial (10). Calculation of differential benefits, if any, of the two SERMs among former users of HRT compared with never users may be both informative and confirmatory. The fact that both ER-positive breast cancers and those that occur during HRT have a favorable prognosis is an observation that requires a mechanistic explanation at the molecular level (11). Additional prospective studies exploring the effect of SERMs in former users of HRT should be conducted.

The results of this current re-analysis of the Italian tamoxifen prevention trial raise many questions: Is there a high-risk group of patients who clinicians can identify in whom tamoxifen has a stronger preventive effect? Which risk factors should define the high-risk group for breast cancer risk reduction? Does it make sense to offer chemoprevention to this group of women? Should women who have discontinued HRT and who are not otherwise at increased risk receive tamoxifen preferentially to reduce their risk?

The strategy of targeting breast cancer risk reduction interventions at high-risk populations is well established (12). Only a small number of patients from the Italian cohort (702 of 5395) were identified as being at high risk using clinical criteria that are not globally accepted. Risk factors such as previous breast biopsies, family history of breast cancer, and age were not included. At the initiation of their trial in 1992, the Italian investigators did not have available to them the validation of the Gail model that was published after their trial began (13). The Gail model is the accepted North American standard for quantifying the risk of breast cancer. Five of the risk factors the Italians used in their subset analyses (age, previous biopsy for benign breast disease, blood relatives with breast cancer, age at menarche, and age at first birth) are components of the Gail model (14). It would have been instructive for the Italian investigators to calculate 5-year risks of developing breast cancer retrospectively for their subjects using the Gail model to facilitate objective comparisons of participants‘ risk status across trials, although their stratifications do permit cautious preliminary assessments.

By contrast with the Italian trial, the North American NSABP-P1 study, which found a 49% risk reduction in high-risk women treated with tamoxifen at 69 months follow-up, identified a high-risk group at the outset of the trial and followed them prospectively (4). These women were older (>60 years), or were between age 35 and 59 years with a predicted risk of developing breast cancer within 5 years of at least 1.66%, according to the Gail model. The Gail model is a multivariable logistic regression model that combines age, number of first-degree relatives with breast cancer, number of breast biopsies, and a history of diagnosis of atypical hyperplasia that are not included in the Italian trial‘s definition of high risk. Common to both definitions of risk are early menarche, nulliparity, and age of first live birth. In the NSABP P-1 study, tamoxifen reduced the risk of invasive breast cancer across all risk strata, regardless of prior use of HRT.

Tamoxifen is most beneficial for younger women with an elevated risk of breast cancer (15). Using tamoxifen in premenopausal women with a uterus does not increase the risk of developing invasive endometrial cancer, and hysterectomy should not be performed for the purpose of eliminating this risk. Weighing risks and benefits in postmenopausal women is more problematic, but among postmenopausal women whose risk of breast cancer is increased, there is net benefit when using tamoxifen even with an intact uterus (16).

After review of these large trials, a uniform theme emerges: tamoxifen is effective chemoprevention against the development of breast cancer in women at high risk. Despite varying definitions of risk, tamoxifen lowered the incidence of breast cancer in three randomized trials involving women at increased risk. Re-analysis of the Italian data—albeit using retrospective subsets—confirms tamoxifen‘s role in breast cancer chemoprevention. What remains unknown is whether this demonstrated reduction in the incidence of breast cancer will ultimately lead to an increased survival or overall health benefit for women at risk, or whether women previously taking HRT should consider tamoxifen for chemoprevention (17). Identifying women who are likely to develop ER-positive breast cancer is important when attempting to maximize the net benefits of tamoxifen use, but using tamoxifen combined with HRT is not recommended outside of a clinical trial setting. Newer agents being evaluated for breast cancer risk reduction such as raloxifene (10) and aromatase inhibitors (18) may offer increased efficacy while not increasing the risk of uterine malignancy. Continued follow-up of the patients in these trials will help to answer these questions in the near future.

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