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Journal of Clinical Oncology, Vol 22, No 14 (July 15), 2004: pp. 2842-2848 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.03.120 Post-Treatment Change in Serum Estrone Predicts Mammographic Percent Density Changes in Women Who Received Combination Estrogen and Progestin in the Postmenopausal Estrogen/Progestin Interventions (PEPI) TrialFrom the Department of Preventive Medicine/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine; David Geffen School of Medicine at University of California, Division of Geriatric Medicine, Los Angeles, CA; Department of Nutrition, University of Oslo, Norway; and Wake Forest University School of Medicine, Department of Public Health Sciences, Winston-Salem, NC Address correspondence to Giske Ursin, MD, PhD, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Room 4407, USC Keck School of Medicine, 1441 Eastlake Ave, Los Angeles, CA 90089; e-mail: gursin{at}usc.edu
PURPOSE: Postmenopausal estrogen and progestin therapy (EPT) increases mammographic percent density and breast cancer risk substantially more than does estrogen therapy alone. We determined whether increases in serum estrone as a function of treatment predict increases in mammographic percent density. METHODS: We measured mammographic percent density and serum estrone levels in participants in the Postmenopausal Estrogen/Progestin Interventions Trial who were randomly assigned to receive conjugated equine estrogens (CEE) 0.625 mg/d; CEE and medroxyprogesterone acetate (MPA) 10 mg on days 1 to 12 per 28-day cycle; CEE and MPA 2.5 mg/d; or CEE and micronized progesterone (MP) 200 mg on days 1 to 12 per 28-day cycle. We used linear regression to determine whether serum estrone changes predicted mammographic percent density changes from baseline to 1 year. RESULTS: Mammographic percent density increased with increasing change in estrone level in the EPT groups, but not in the CEE group. Combined, the mammographic percent density in the three EPT groups demonstrated an absolute increase of 2.95% per 100 pg/mL increase in serum estrone level (P = .0003). The absolute increases were 4.09% (P = .0018) in the CEE + MPA continuous group, 2.79% (P = .0292) in the CEE + MPA cyclical group, and 1.40% (P = .36) in the CEE + MP group, but the differences among the EPT groups were not statistically significant. CONCLUSION: Greater increase in serum estrone level as a function of treatment is a significant predictor of increase in mammographic percent density in women randomly assigned to the combination of estrogen and progestin.
There is growing epidemiologic evidence that combined estrogen and progestin therapy (EPT) increases the risk of breast cancer substantially more than estrogen therapy (ET) alone.1-8 We published results from two Postmenopausal Estrogen/Progestin Interventions (PEPI) mammographic percent density studies showing that average mammographic percent density increased in women in the combined EPT groups but not in the ET-alone group,9,10 and that there was substantial variation in the amount of density change within each treatment group. Mammographic percent density represents a strong breast cancer risk factor.11-14 Although the clinical significance of a change in mammographic percent density is unclear, it is plausible that women with a large mammographic percent density increase may be more likely to develop breast cancer as a result of the EPT than women with no such increase. Even if this is not true, the sensitivity of dense mammograms is substantially poorer than that of nondense mammograms.15 It is therefore important to identify predictors of density increase in women treated with postmenopausal hormone therapy. It seems logical that variations in endogenous hormone levels resulting from hormone therapy would be important. Because both the ET and EPT groups in PEPI received the same estrogen component, we decided to determine whether there were variations in estrogen levels between the ET and EPT groups, and also to determine to what extent variations in estrogen changes predicted mammographic percent density increase as a result of hormone therapy. An important metabolite from conjugated estrogens is estrone.16,17 One of the aims in our National Cancer Institute–funded project was to examine whether changes in measured serum estrone levels due to treatment could be a predictor of mammographic percent density change in the hormone therapy groups.
Parent Study The study design has been described in detail previously.9,10 Briefly, the PEPI trial enrolled 875 postmenopausal women aged 45 to 64 years in a 3-year trial at seven United States clinical centers between 1989 and 1991. All randomized eligible participants had not had any menstrual periods during the previous 12 months, had not used estrogens or progestins in the past 2 months, and had a follicle-stimulating hormone level of more than 40 mU/mL. For a complete list of inclusion criteria, see Espeland et al.18 Participants were randomly assigned to receive one of the following treatments: placebo; conjugated equine estrogens 0.625 mg/d (CEE); CEE and medroxyprogesterone acetate (MPA) 10 mg on days 1 to 12 per 28-day cycle (CEE + MPA cyclic); CEE and MPA 2.5 mg/d (CEE + MPA continuous); or CEE and micronized progesterone (MP) 200 mg on days 1 to 12 per 28-day cycle (CEE + MP). Demographics, medical history, physical activity, lifetime use of cigarettes, contraceptive and noncontraceptive estrogen and progestin use, as well as alcohol intake, were assessed using standardized questionnaires. The participants were asked to assess their home, work, and leisure physical activity performed in the last 12 months rated on a scale from 0 to 3 defined as inactive, light, moderate, and heavy, respectively.19 The physical activity variable was created by taking a mean of the leisure and home scores. Tertiles for physical activity and alcohol intake were created on the basis of the entire PEPI sample of 875 women. Height and weight were measured with participants wearing light clothing and no shoes. Body mass index (BMI) was calculated as body weight in kilograms divided by the square of height in meters. Medications and placebos were blister packed and unused pills were counted at each visit.
Mammographic Percent Density Substudy The mammographic percent density measurements of this study have been described in detail previously.9 In brief, left breast craniocaudal baseline and follow-up mammograms were scanned at a resolution of 150 pixels/inch (59 dots/cm) using a Cobrascan CX-312T scanner (Radiographic Digital Imaging Inc, Compton, CA) and Adobe Photoshop software (Adobe, San Jose, CA) with the plug-in program Scanwizard 3.0.9 (Microtek, Hsinchu, Taiwan). Mammographic percent density was assessed by G. Ursin, who was blinded to treatment, study visit, and which mammograms belonged to the same patient. Mammograms from the same patient were read in the same setting, in a random order. The density assessments were conducted using a validated computer-assisted, quantitative method.20 In brief, on the digitized mammographic image displayed on the computer screen, the reader first outlines the entire breast using an outlining tool, and then uses a tinting tool to color areas considered to contain mammographic densities, while excluding the pectoralis muscle and other artifacts. The software counts the number of tinted pixels and the total number of pixels in the breast. The mammographic percent density is the ratio of these two numbers. This method correlates highly with the expert outlining method used in planimetry-based studies,12,21,22 and is a strong predictor of breast cancer risk.14 We estimated change in mammographic percent density as an absolute change in mammographic percent density (ie, this equals mammographic percent density at follow-up minus mammographic percent density at baseline).
Serum Estrone Measurements
Statistical Analysis
Table 1 lists basic characteristics of the participants by treatment group. There were no statistically significant differences in age, race, baseline BMI, 12-month change in BMI, hysterectomy status, baseline physical activity, adherence to treatment, and baseline mammographic percent density among the four active treatment groups or between women in the EPT groups combined compared with women in the CEE group. There were statistically significant differences among women in the four active treatment groups in baseline smoking status (P = .03), level of alcohol intake (P = .03), and change in mammographic percent density (P = .009).
We examined the changes in percent density by baseline percent density in the CEE and EPT arm, but found no obvious trend in either treatment arm. Pearson correlation coefficients between change in percent density and baseline percent density were –0.141 in the CEE arm and –0.169 in the EPT arm (data not shown). The mean baseline, 12-month, and 12-month change in serum estrone levels in women by treatment group are listed in Table 2. There were no statistically significant differences in baseline serum estrone levels among the four active treatment groups or between women in the CEE group and the three EPT groups combined. The highest serum estrone level at 12 months and the largest increase in serum estrone occurred in women in the CEE group; the lowest change in estrone occurred in women in the CEE + MP group, but there were no statistically significant differences in 12-month follow-up or change in estrone values among treatments (all P  0.09).
Figure 1 shows unadjusted changes in percent density by change in serum estrone in the EPT arm and the CEE arm. Although the relation between change in serum estrone level and change in mammographic percent density seems to be curvilinear, this appearance is driven by a single observation with an estrone value of 415 pg/mL. The adjusted mean absolute changes in percent mammographic percent density for each 100 pg/mL change in estrone by treatment group are listed in Table 3. There was no statistically significant association between mammographic percent density change and estrone change in the CEE group (P > .90). However, in the EPT groups combined there was a 2.95% increase in mammographic percent density per 100 pg/mL increase in estrone (P = .0003). The increases were 4.09% (P = .0018) in the CEE + MPA continuous group, 2.79% (P = .0292) in the CEE + MPA cyclical group, and 1.40% (P = .36) in the CEE + MP group, but the differences between the EPT groups were not statistically significant. These differences in mammographic percent density were due primarily to changes in the dense area of the breast. The adjusted mean increase in dense area for the EPT groups combined was statistically significant (P = .0009), whereas the changes in total nondense area did not quite reach statistical significance in any group.
Figure 2 shows the baseline and 12-month follow-up mammograms for the two women with the greatest absolute percent mammographic percent density changes (57% and 34%, respectively) who were randomly assigned to receive EPT. Serum estrone increased 191 and 236 pg/mL, respectively, in these two women.
Mammographic percent density increase was significantly and positively associated with serum estrone increase in women in the EPT group, but not in women in the CEE group. The changes in mammographic percent density were due primarily to an increase in the dense area of the breast in women in the EPT group. The changes in serum estrone from baseline (pretreatment) to 12 months were similar in the CEE group and the EPT groups. Serum estrone increased slightly less in the progestin groups than in the CEE-only group, but this was not statistically significant. Thus the association between serum estrone increase and mammographic percent density increase in the EPT groups was not due to larger estrone changes in the EPT groups. Mammographic percent density represents a strong, independent risk factor for breast cancer,12,14,21,22,24-26 and it has been estimated that the relative risk of breast cancer increases approximately 2% for every 1% increase in density.26 However, the clinical significance of a change in mammographic percent density is unknown. Mammographic percent density changes may reflect cell proliferation changes in the breast.27 The fact that the change in mammographic percent density was predominantly caused by an increase in the dense area, rather than a decrease in the nondense area, supports this hypothesis. We have postulated previously that an increase in mammographic percent density may be a marker for the subset of women whose breast cancer risk is increased by postmenopausal hormone use.9 An alternative hypothesis would be that the effect of EPT use on breast cancer risk is not mediated through mammographic density, and that the clinical implications of the mammographic density changes with EPT use is simply that it results in abnormal mammograms,8 making a cancer more difficult to detect. Although the first hypothesis may seem more likely, the distinction between these two hypotheses can only be tested by examining the breast cancer risk in women who develop mammographic density increase while receiving EPT. The lack of association between serum estrone change and mammographic percent density in the CEE-only group suggests that an increase in estrone alone does not significantly increase mammographic percent density. This is consistent with the growing evidence that EPT causes much greater increased breast cancer risk than ET alone,1-8 and that breast cell proliferation is higher in women receiving EPT than in women receiving ET alone.28 In contrast, the degree of change in serum estrone in those taking CEE plus a progestin was associated with the amount of mammographic percent density increase. One hypothesis to explain this finding would be that serum estrone changes are correlated with changes in progestin levels, and that a greater change in estrogen and progestin combined is associated with greater breast cell proliferation and therefore mammographic percent density changes. We did not measure progestin or MPA levels, thus we cannot test this theory. It also is possible that a greater change in serum estrone results in higher levels of estrogen-induced progesterone receptor expression,29 which in turn augments the effect of EPT on breast cell proliferation. Either way, assuming mammographic percent density change is a marker for changes in breast cancer risk, our findings of serum estrone predicting mammographic percent density increase in EPT users could be interpreted to suggest that women with a higher effective EPT dose will be at higher risk of breast cancer. The magnitude of the density increase we observed can be compared with what we know about the effect of other hormonal interventions on mammographic percent density. The reduction in mammographic percent density was 9.4% in women randomly assigned to receive tamoxifen (20 mg/d) and 3.6% in the placebo group in a Canadian trial of women at high risk of breast cancer.30 Interestingly, the difference between these groups, 5.8%, is only about twice the change we observed per 100 pg/mL change in serum estrone. Thus, the average changes we observe in this study are not that different from what has been observed previously with hormonal interventions expected to reduce breast cancer risk, and are therefore not inconsequential. Furthermore, as we demonstrated in Fig 2, the mammographic percent density changes were quite substantial in some women. Conversely, if women with smaller increases in serum estrone from EPT have smaller mammographic percent density changes, then this suggests that at lower serum levels (or effective dose) of these medications, EPT might not be harmful to the breast. The differences in mammographic changes among the three EPT regimens in our study were not statistically significant, and additional work will be needed to determine whether these regimens confer differences in mammographic percent density as well as differences in breast cancer risk. We measured only changes in serum estrone as a function of treatment. Estrone is an important16 compound in CEE, standardly used as a marker for CEE,17 but there are other active estrogens in CEE as well.31 Failure to measure additional important compounds could have led us to underestimate the correlation between changes in levels of estrogenic compounds in serum and mammographic percent density changes. However, we would have expected this underestimate to be of similar magnitude regardless of treatment group, and this is therefore unlikely to explain the described differences in mammographic percent density response between the different treatment groups. In conclusion, measured change in serum estrone level 1 year after starting therapy with CEE is not associated with substantial change in mammographic percent density. In contrast, in the combination hormone preparations tested in this study, there was a strong relation between measured change in serum estrone level after 1 year of treatment and increase in mammographic percent density. Our results are consistent with the evidence suggesting that ET only increases breast cancer risk slightly, but that the combination of estrogen and progestin has a much greater effect on breast cancer risk. Additional research is needed to determine whether mammographic density increase is a good predictor of breast cancer risk in EPT users. Additional research also is needed to determine whether women with a higher effective EPT dose are at higher risk of breast cancer, and whether EPT dose can be individualized to reduce the harmful effects of EPT.
The authors indicated no potential conflicts of interest.
Supported by grant funding from the National Cancer Institute, R-01 CA 77708, and by P30CA14089 (M.C.P.). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
