- © 2012 by American Society of Clinical Oncology
Suppression of Plasma Estrogen Levels by Letrozole and Anastrozole Is Related to Body Mass Index in Patients With Breast Cancer
- Elizabeth J. Folkerd and Mitch Dowsett, Royal Marsden Hospital, London; J. Michael Dixon and Lorna Renshaw, Western General Hospital, Edinburgh; and Roger P. A'Hern, Institute for Cancer Research, Sutton, United Kingdom.
- Corresponding author: Elizabeth J. Folkerd, PhD, Academic Department of Biochemistry, The Royal Marsden NHS Foundation Trust, Fulham Rd, London, SW3 6JJ, United Kingdom; e-mail: Elizabeth.Folkerd{at}icr.ac.uk.
Abstract
Purpose To investigate whether suppression of plasma estradiol and estrone sulfate levels by the aromatase inhibitors (AIs) anastrozole and letrozole is related to body mass index (BMI) in postmenopausal women with early estrogen receptor (ER) –positive breast cancer. Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI. This effect with high BMI might hypothetically be a result of reduced inhibition of aromatase and suppression of plasma estrogen levels and might be overcome by the use of an increased dose of anastrozole or, alternatively, the use of a more potent AI such as letrozole.
Patients and Methods Plasma estradiol and estrone sulfate levels from a highly sensitive radioimmunoassay were available for 44 postmenopausal patients who received anastrozole (1 mg per day) for 3 months followed by letrozole (2.5 mg per day) for 3 months or the opposite sequence. Correlations between the estrogen suppression by each AI and BMI were assessed.
Results Baseline values of estradiol and estrone sulfate were significantly correlated with BMI (r = 0.57; P < .001, and r = 0.38; P = .006, respectively). Levels of estrogen in patients receiving treatment were greater at higher levels of BMI with both AIs, but although this was significant with letrozole (r = 0.35; P = .013, and r = 0.30; P = .035 for estradiol and estrone sulfate, respectively), it was not with anastrozole. Suppression of both estrogen types was greater with letrozole across the full range of BMIs in this study.
Conclusion The suppressed levels of plasma estradiol and estrone sulfate in postmenopausal women with early ER-positive breast cancer treated with the AIs anastrozole and letrozole are related to BMI.
INTRODUCTION
High body mass index (BMI) has long been known to be a risk factor for breast cancer in postmenopausal women.1 Recent reports2,3 have demonstrated an association between obesity and both increased risk of recurrence and mortality, including breast cancer–specific mortality, in women with breast cancer. Understanding the impact and efficacy of chemotherapy and endocrine treatment dosing in relation to patients with breast cancer who are overweight is an important area for investigation: the findings could result in the modification of therapeutic regimens and improvement in outcome for obese women with breast cancer. Two recent studies4,5 have reported that patients with a higher BMI experience reduced efficacy of the aromatase inhibitor (AI) anastrozole relative to tamoxifen when these drugs are administered as adjuvant therapy for early estrogen receptor (ER) –positive breast cancer.
Postmenopausal women with ER-positive breast cancer who participated in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial who had a high BMI (> 35 kg/m2) before treatment had a greater chance of recurrence and death after recurrence than those with a low baseline BMI (< 23 kg/m2).4 In addition, the relative benefit of anastrozole compared with tamoxifen was less in overweight women: the adjusted hazard ratio for distant recurrence was 0.59 (95% CI, 0.39 to 0.89) in favor of anastrozole in women with a BMI of less than 23 kg/m2 compared with 0.96 (95% CI, 0.61 to 1.14) for those with a BMI of greater than 30 kg/m2. More recently, the Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12) compared the outcomes of anastrozole with tamoxifen in premenopausal women undergoing ovarian suppression with the gonadotropin-releasing hormone agonist goserelin.5 Disease-free survival was similar for anastrozole and tamoxifen in normal-weight patients, but in overweight patients there was a 49% greater risk of recurrence with anastrozole compared with tamoxifen (P = .08). In both reports it was suggested that the higher levels of peripheral aromatase in obese women might result in reduced effectiveness of anastrozole at its usual 1 mg per day dose and that higher doses or more complete inhibition of aromatase might be more effective in such women. An alternative to a higher dose of anastrozole would be to use an AI with greater efficacy in suppressing estrogen production.
Letrozole is a more potent inhibitor of aromatase than anastrozole, and at their conventionally used doses, letrozole leads to more complete inhibition of whole-body aromatase (> 99% compared with 97%, respectively).6 Our previously published endocrine data from the ALIQUOT (Anastrozole vs Letrozole, an Investigation of Quality Of Life and Tolerability) study7 demonstrated clearly that letrozole suppresses plasma estradiol and estrone sulfate levels more completely than anastrozole. In this study, we have analyzed the estrogen data from the ALIQUOT study in relation to BMI to determine whether there is any evidence of incomplete suppression of plasma estrogens by anastrozole in heavier women, and if there is such evidence, whether incomplete suppression can be overcome by the greater potency of letrozole in suppressing aromatase.
PATIENTS AND METHODS
The details of the ALIQUOT study and the methodologies for plasma estrogen analysis have been published previously. In brief, ALIQUOT was an open-label, cross-over study of 54 postmenopausal women with hormone receptor–positive breast cancer who received adjuvant aromatase inhibition. Patients were randomly assigned to receive either 3 months of anastrozole (1 mg per day) followed by 3 months of letrozole (2.5 mg per day), or the opposite sequence, so that estrogen values were available for both agents. Twenty-seven patients initiated treatment with anastrozole and 27 with letrozole. The mean age was 63 years (range, 49 to 83 years). None of the patients had received previous treatment with chemotherapy. Half of the patients had received 5 years of adjuvant tamoxifen before AI therapy. There was no significant difference in estrogen levels either at baseline or during AI treatment between the patients who had received tamoxifen previously and those who had not received tamoxifen.7
Blood samples were collected after an overnight fast at the same time of day before and after each course of AI. Plasma estradiol was measured using an assay with a conventional sensitivity limit of 3 pmol/L. As described previously,7 in this study, values below this limit were estimated for within-patient comparisons by extrapolation of the counter-derived spline-fit of percentage radioactivity-bound versus log-dose. Plasma estrone sulfate was measured as estrone after hydrolysis of the estrone sulfate to estrone and column chromatographic purification. The sensitivity limit of the assay was 15 pmol/L. BMI data were not available for two of the patients, and the serum estradiol measurements from 10 additional patients were excluded because the precision of the estradiol measurements was outside of the acceptable range. Of the 54 patients in the ALIQUOT study, complete data regarding BMI and estrogen measurements were available for 44 patients.
Statistical Methods
The relationship between BMI and plasma estrogen levels was assessed by Spearman rank correlation.
RESULTS
Data were analyzed without regard to the order in which the respective AIs were received because this had no significant influence on relative suppression with the two agents. Overall, letrozole reduced the estradiol levels by an additional 43% compared with anastrozole and reduced estrone sulfate levels by an additional 58% compared with anastrozole.
The relationships of estradiol and estrone sulfate with BMI are summarized in Tables 1 and 2 , and individual values for plasma estrogens are shown in Figure 1. Baseline estradiol levels correlated with BMI when examined by regression analysis (r = 0.57; P < .001). Baseline values were nearly three times higher in women with BMIs of greater than 35 kg/m2 compared with women with BMIs of less than 25 kg/m2. Weaker, positive correlations were found between BMI and on-treatment estradiol levels with letrozole (r = 0.35; P = .013) and showed a similar trend but were not statistically significant for anastrozole (r = 0.21; P = .14). The relative levels of residual estradiol during treatment with anastrozole were consistently higher than those during treatment with letrozole: letrozole suppressed plasma estradiol levels to a greater degree compared with anastrozole across the entire range of BMIs.
ALIQUOT Study7: Relationship Between BMI and Serum Estradiol Levels in Response to AI Treatment
ALIQUOT Study7: Relationship Between BMI and Serum Estrone Sulphate Levels in Response to AI Treatment
On-treatment values (pmol/L) of plasma (A) estradiol (E2) and (B) estrone sulfate (E1S) after 3 months of treatment with anastrozole or letrozole according to body mass index (BMI).
Similar results were seen with estrone sulfate. The correlation between baseline values of estrone sulfate and BMI was 0.38 (P = .006); values in the highest BMI category were nearly three-fold higher than those in the lowest. Although there was a trend for estrone sulfate levels to be higher after anastrozole treatment at the higher BMI values, the correlation was weak and was not statistically significant. With letrozole, the correlation was stronger and statistically significant (r = 0.30; P = .035). As shown in Table 2 for all four BMI categories, estrone sulfate suppression was greater with letrozole than with anastrozole. This difference was 4.6-fold greater for the highest category of BMI, but it was 3.8-fold even for the lowest category.
DISCUSSION
AIs are more effective agents than tamoxifen in preventing recurrence in postmenopausal women with early ER-positive breast cancer.8 This improved activity has been recently shown to extend to reduced mortality with letrozole.9 Rates of obesity have increased markedly in the recent past, and aromatase activity and plasma estrogen levels are higher in obese postmenopausal women.1,10 The relationship between risk of postmenopausal breast cancer and BMI has been found to be largely (but probably not entirely) explained by the higher plasma levels of estradiol.1 Given that AIs act by the suppression of estrogen synthesis and withdrawal of estrogenic growth support to ER-positive breast cancer, it was reasonable to hypothesize that the reduced efficacy of anastrozole relative to tamoxifen in the ATAC and ABCSG-12 studies in obese women might be a result of poorer suppression of plasma estrogen levels at higher levels with anastrozole.8,5 Our previously reported data from the randomized cross-over ALIQUOT study provided an ideal opportunity to assess not only whether anastrozole had lower pharmacologic effectiveness at high levels of BMI but also whether the more potent inhibitor letrozole might overcome this possible deficiency. It is notable that letrozole has an approximately 10-fold higher potency than anastrozole11,12 and is also used at a 2.5-fold higher dose; this therefore provides a substantial increase in pharmacologic activity.
Our data have confirmed the significant positive relationship between estrogen levels and BMI in untreated patients. This positive relationship was found to extend to estrogen levels during treatment with AIs and BMI. Although letrozole suppressed plasma estradiol and estrone sulfate levels to a greater degree than anastrozole in all of the categories of BMI investigated, there was no suggestion that the effect of letrozole was proportionally greater when treating obese women compared with normal-weight women. In fact, the positive correlation between estrogen levels and BMI was stronger in letrozole-treated than in anastrozole-treated patients. However, it is notable that the 95% CI for the correlation coefficient with anastrozole extended to 0.46 and 0.34 for estradiol and estrone sulfate, respectively, which overlaps with the coefficients for letrozole in both cases.
There are two key issues that could potentially limit the validity of this research. First, this study was relatively small, with between five and 16 patients in each BMI category, and would therefore benefit from being repeated in a larger population. Second, it is possible that noncompliance could have influenced the observations. However, patients in the study were regularly questioned to confirm compliance. In addition, the consistent differences in estrogen suppression between letrozole and anastrozole support that there was high compliance during the period of study.
There has been substantial debate about the relative relevance of plasma and intratumoral estrogen levels and their inhibition, but recent articles indicate that plasma estrogens probably play a dominant role.12a Although estradiol is the most potent estrogen, its low levels in postmenopausal women, particularly in those treated with an AI, make its accurate measurement challenging. Whereas estrone sulfate has no direct stimulatory role, its synthesis is initially dependent on aromatase, and its much higher plasma levels potentially allow its suppression to reflect degrees of inhibition with greater reliability. In the ALIQUOT study, we took the unusual step of accepting estradiol data that in many cases were below the formal sensitivity limit of the assay. The highly consistent finding using this approach was that in 52 of the 54 patients, there was greater suppression with letrozole than with anastrozole, which fits in well with other reported data and suggests that the results from this assay are informative even at low levels.7
Indirect comparisons from clinical studies have indicated that the degree of aromatase inhibition does correlate with clinical efficacy and explains improvements seen clinically from first-, to second-, and then to third-generation AIs.13 Although the suppression of plasma estrogen levels is significantly greater with letrozole than with anastrozole across the entire range of BMIs in this study, it is not known whether the differences in the degree of suppression with these two third-generation inhibitors is of clinical significance. Direct data on this issue will be available from the ongoing Femara Anastrozole Clinical Evaluation (FACE) trial, which is comparing the efficacy and tolerability of these two agents in early breast cancer.
Thus, our data support that higher estrogen levels occur in women with higher BMIs during treatment with AIs, and this may at least contribute to the poorer benefit seen from anastrozole versus tamoxifen in such women in the ATAC and ABCSG-12 trials. However, alternative hypotheses to explain the relative efficacy of tamoxifen versus anastrozole in patients with higher BMIs should also be considered. These include the possibility that it is not the effectiveness of the AI per se that is affected by BMI, but rather, that there may be reduced apparent agonist activity of tamoxifen at higher levels of estrogen and hence of BMI. Significant agonist activity of tamoxifen in ER-positive breast cancer has been proposed as a likely explanation of the worse outcome of patients treated with anastrozole plus tamoxifen versus anastrozole alone.14 Variability in the agonist-antagonist balance of tamoxifen according to prevalent estrogen levels is seen in animal models, with uterine weight being increased by tamoxifen at low estrogen levels but decreased at high estrogen levels.15 Similar observations have been made in patients with breast cancer: tamoxifen increases bone density in postmenopausal women, whereas it decreases it in premenopausal women,16 and tamoxifen increases plasma gonadotrophin levels in premenopausal women but decreases them in postmenopausal women.17,18 The differential benefit seen between anastrozole and tamoxifen according to BMI may therefore be a result of at least two factors: differential suppression of estrogen levels by the AI and the variable agonist-antagonist balance seen with tamoxifen according to endogenous estrogen levels.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Mitch Dowsett, AstraZeneca (C) Stock Ownership: None Honoraria: Mitch Dowsett, AstraZeneca Research Funding: Mitch Dowsett, AstraZeneca, Novartis Expert Testimony: Mitch Dowsett, AstraZeneca Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: J. Michael Dixon, Mitch Dowsett
Provision of study materials or patients: Lorna Renshaw
Collection and assembly of data: J. Michael Dixon, Lorna Renshaw
Data analysis and interpretation: Elizabeth J. Folkerd, Roger P. A'Hern, Mitch Dowsett
Manuscript writing: All authors
Final approval of manuscript: All authors
Acknowledgment
We thank Rowan Chlebowski, MD, PhD, whose discussions prompted this analysis, and The Royal Marsden National Institute for Health Research Biomedical Research Centre and Breakthrough Breast Cancer for their support.
Footnotes
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See accompanying editorial on page 2940
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
- Received January 26, 2012.
- Accepted May 15, 2012.
