Original Study
Does Obesity Interfere With Anastrozole Treatment? Positive Association Between Body Mass Index and Anastrozole Plasma Levels Michael Hubalek,1 Anne Oberguggenberger,2 Beate Beer,3 Verena Meraner,2 Monika Sztankay,2 Herbert Oberacher,3 Birthe Schubert,3 Ludwig Wildt,4 Beata Seeber,4 Johannes Giesinger,2 Georg Kemmler,2 Bernhard Holzner,2 Barbara Sperner-Unterweger2 Abstract Previous research suggests that anastrozole treatment efficacy is associated with body mass index (BMI). This study investigated pharmacokinetic aspects of anastrozole and BMI in 235 patients with breast cancer and found BMI to be a vital component in anastrozole metabolism, as indicated by anastrozole plasma concentration. Nevertheless, women with obesity still displayed higher estrogenic activity compared with those without obesity. Introduction: The efficacy of adjuvant endocrine treatment with aromatase inhibitors (AIs), inhibiting the conversion of androgens to estrogen in adipose tissue, might depend on the overall volume of adipose tissue. However, little evidence is available regarding the pharmacokinetic behavior of AIs in women with obesity. The aim of this study was to investigate the interaction between body mass index (BMI) and anastrozole treatment as well as estrogenic activity. Patients and Methods: A total of 216 postmenopausal patients with early-stage breast cancer who were receiving AI treatment with anastrozole constituted the final sample included in the analysis. During a regular 3-month after-care check-up, sociodemographic and clinical data and BMI were assessed. Blood samples were collected during routine blood testing. Measurement of AI plasma levels was performed by liquid chromatographyetandem mass spectrometry. Follicle stimulating hormone (FSH) and estradiol were measured within the routine blood examination. Results: A median anastrozole plasma concentration of 34.7 ng/mL (mean, 37.4), with a large interindividual variability, was observed (SD, 15.1; range, 5.4-86.5). After age adjustment, it was found that anastrozole plasma concentrations significantly increased with BMI (r ¼ 0.241; P ¼ .001). Anastrozole serum concentrations in women with obesity (BMI 30) exceeded those of women with normal weight (BMI 25) by 25%. Women with excess weight had lower mean FSH levels, indicating higher estrogenic activity, compared with women with normal weight. Conclusion: This study indicates that BMI is a vital factor in anastrozole metabolism, as measured by anastrozole plasma concentration and FSH levels. Further research is mandatory to clarify results on the association of obesity and AI treatment efficacy to allow adapting AI treatment accordingly. Clinical Breast Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Anastrozole treatment efficacy, Aromatase inhibitor, Aromatase inhibitor, Association of BMI and AI plasma concentrations, Breast cancer, BMI, Levels
M. Hubalek and A. Oberguggenberger contributed equally to this work as first authors. 1
Department of Obstetrics and Gynecology 2 Department of Psychiatry and Psychotherapy 3 Institute of Legal Medicine and Core Facility Metabolomics 4 Department of Gynecological Endocrinology and Reproductive Medicine Innsbruck Medical University, Innsbruck, Austria Submitted: Sep 24, 2013; Revised: Dec 23, 2013; Accepted: Dec 23, 2013 Address for correspondence: Michael Hubalek, Department of Gynecology and Obstetrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria E-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.12.008
Introduction Recent findings regarding the effect of obesity on the efficacy of adjuvant endocrine treatment with aromatase inhibitors (AIs) for early-stage breast cancer have added to the debate on whether women with obesity benefit less from AI treatment in terms of disease-free survival and overall survival.1 It is a well-known fact that obesity increases total-body aromatization and leads to increased estrogen levels in women with obesity compared with age-matched women with normal or low weight.2 The question has been raised
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BMI and Anastrozole Plasma Levels if standardized dosing of anastrozole might be insufficient to adequately suppress heightened aromatization related to obesity. Overall, little evidence in this regard has been reported, and the available studies yielded inconclusive results.1,3-6 Although initial findings7-9 suggested no association of body mass index (BMI) and AI efficacy in patients with metastatic disease, results from the ATAC trial (Arimidex and Tamoxifen Alone or in Combination) indicate lower efficacy of anastrozole treatment in women with obesity (BMI > 30) in terms of time to recurrence.3 This is in accordance with the findings of Ewertz et al,4 who investigated the efficacy of AIs in correlation with weight and found a survival benefit for women with a BMI < 30 after 10 years of follow-up. No group differences were found for the first 10 years of follow-up. Finally, Pfeiler et al1 observed a 60% relative increase in risk for disease recurrence as well as a 2-fold increase in the risk for death in patients with excess weight compared with those with normal weight receiving anastrozole therapy in the ABCSG 12 trial (Austrian Breast and Colorectal Cancer Study Group trial 12). The authors strongly suggest that incomplete estrogen serum level suppression through inadequate anastrozole dosing explains these findings, and they assume an AI dose adjustment according to body weight to be essential for the optimization of treatment efficacy. Nonetheless, evidence is lacking about patterns of anastrozole pharmacokinetics in correlation with obesity. To the best of the authors’ knowledge, there is no observational study on AI plasma concentrations related to BMI available that illustrates altered anastrozole elimination in women with obesity. Additionally, the authors evaluated follicle stimulating hormone (FSH) levels as a surrogate marker for estrogenic activity.10 The purpose of this study was to contribute to the clarification of the interaction of anastrozole treatment and obesity. Thus, the following research question was addressed: Are anastrozole plasma concentrations associated with BMI? Ethical approval for this project was obtained from the Ethics Committee of the Innsbruck Medical University.
Patients and Methods Sample This cross-sectional study was performed at the outpatient unit of the Department of Gynecology and Obstetrics. Patients with breast cancer were found eligible when meeting the following inclusion criteria: a diagnosis of breast cancer stage I to III; adjuvant endocrine therapy with anastrozole for at least 2 weeks after primary surgery for breast cancer; postmenopausal state; maximum age of 85 years; no recurrent or metastatic disease; no overt cognitive impairment; no previous treatment with antihormonal medication; and written informed consent.
Physical Examination Data Weight (to the nearest 0.5 kg) and height (to the nearest 0.5 cm) were measured while the patient underwent routine follow-up examination for breast cancer. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters (kg/m2). Patients were assigned, according to their BMI, to 1 of 3 groups: those with normal weight (BMI 25), those who were overweight (BMI > 25 and 30), and those with obesity (BMI > 30).
Laboratory Data Blood samples were collected at one of the patient’s routine follow-up visits (which are done every 3 months) within the course of endocrine treatment (ranging from 3 to 89 months after treatment initiation). Mean treatment duration was 30.6 months. Liver function parameters and kidney function parameters were measured by standard and quality-controlled procedures. Hepatic function was indicated by gamma glutamyl transferase (gGT), alanine aminotransferase, aspartate aminotransferase, bilirubin, lactate dehydrogenase, and albumin; renal function was investigated by creatinine and urea. Creatinine clearance was estimated by using the Cockcroft-Gault formula.11 Additionally, estradiol and FSH levels were measured as part of the routine laboratory examination of the central laboratory, with kits for electrochemiluminescence immunoassays (Roche Diagnostics) on an automated analyzer (Modular E170 Immunology Analyzer; Roche Analytics). The detection limit for estradiol was 12 pg/mL at the central laboratory. However, almost all measured sera exhibited estradiol levels under the detection limit. AI plasma concentrations were determined by a fully validated liquid chromatographyetandem mass spectrometry (LC-MS/MS) method published elsewhere.12 To prepare the collected samples for LC-MS/MS analysis, 1 mL plasma was treated with a solid phase extraction procedure using a cation mixed-mode polymeric sorbent phase (Strata-X-C cartridges; Phenomenex, Torrance, CA). Chromatographic separation was accomplished on a reversed-phase column (200 mm 0.5 mm, Eurospher C18, 5 mm; Knauer, Berlin, Germany) by using a gradient of acetone in an aqueous hexafluorobutyric acid solution. Tandem mass spectrometric detection was performed on a quadrupole-quadrupole-linear ion trap instrument (3200 Q Trap; Applied Biosystems/Life Technologies). The mass spectrometer was operated in the positive ion mode with a TurboIonSpray source (Applied Biosystems/Life Technologies). Multiple reaction monitoring was performed using the precursor-to-product ion transitions m/z 294.2/225.2 (quantitative) and 294.2/210.1 (qualitative) for anastrozole, 286.2/217.1 (quantitative) and 286.2/190.2 (qualitative) for letrozole, and 249.3/193.2 (quantitative) and 249.3/175.2 (qualitative) for the internal standard bunitrolol.
Procedure
2
-
Eligible patients were identified by a search of the medical records. Eligible patients were approached during a standard after-care check-up at the outpatient unit of the Department of Gynecology and Obstetrics. These patients were informed about the study, and each provided written informed consent. Blood samples were collected as part of routine blood testing (as described later). Plasma was then stored at 80 C until the analysis of AI levels. Routine parameters were measured immediately.
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Statistical Analysis Characteristics of the study population were grouped according to low BMI ( 25) and high BMI (> 25) and were reported as percentages, ranges, means, and standard deviations. The Student t test, Mann-Whitney U test, and c2 test were used to compare differences between groups, as appropriate. Partial correlations were used for determining the association of anastrozole plasma levels with BMI, correcting for age. Univariate correlation analyses
Michael Hubalek et al between anastrozole levels and liver function parameters and kidney function parameters were performed with Spearman and Pearson correlation, as appropriate. Patients with values less than the lower limit of quantitation (c < LLOQ) were classified as nonadherent and were excluded from the analysis. The effect of hepatic and renal function on anastrozole levels was further investigated by means of linear regression analysis.
Results Patient Characteristics Between June 2009 and October 2010, 235 patients were included in the study. For 15 patients, no blood samples could be gathered (owing to logistic reasons), and 4 patients were excluded from the analysis due to anastrozole plasma concentrations below the LLOQ. A total of 216 patients with early-stage breast cancer and receiving anastrozole therapy for a mean duration of 30.4 months (SD, 20.4) constituted the final sample included for the analysis. Data on BMI were available for only 177 patients, owing to logistic reasons in the follow-up setting. The most frequent histopathologic cancer type in this study sample was invasive ductal carcinoma (76.4%) and grade II carcinoma (73.1%). Patients were aged between 46 and 84 years, with a mean patient age of 65.2 (SD, 7.9). A median BMI of 26.1 (SD, 4.5) was observed; 2 (0.9%) patients were underweight, and 26 (12%) were obese, according to World Health Organization definitions.13 Further details are presented in Table 1. Patients with normal weight (BMI 25) were further compared with patients with excess weight (BMI > 25) regarding their sociodemographic and clinical data. No significant group differences were found for any of the collected patient characteristics.
Association of BMI and AI Plasma Concentrations A median anastrozole plasma concentration of 34.7 ng/mL (mean, 37.4; SD, 15.1) was observed. A range of 5.4 to 86.5 ng/mL for AI plasma levels showed a large interindividual variability. After correcting for age, anastrozole plasma concentration significantly increased as BMI increased (r ¼ 0.241; P ¼ .001) (Fig. 1; Table 2).
Effect of BMI on Serum FSH Levels Additionally, the effect of BMI was also indicated by a significant negative association of BMI and FSH (r ¼ 0.289; P ¼ .005), which was evident also after correcting for anastrozole plasma concentration using partial correlation (r ¼ 0.265; P ¼ .011). The mean FSH levels (which can be seen as a surrogate marker for estrogenic activity) of women with obesity were significantly lower than the levels of women without obesity, indicating a higher estrogenic activity in the former (Fig. 2). Owing to the detection limit of the routine assay used to determine estradiol levels, estradiol levels adequate for the investigation of the subject addressed herein could not be obtained.
Effect of Hepatic and Renal Function on AI Serum Concentration The effect of hepatic and renal function on AI serum concentration was investigated using regression analysis. Independent variables included BMI, gGT, alanine aminotransferase, aspartate aminotransferase, bilirubin, lactate dehydrogenase, albumin, total
Table 1 Sociodemographic and Clinical Data All (n [ 216)
BMI £25 (n [ 88)
BMI >25 (n [ 89)
Frequency (%) Frequency (%) Frequency (%) Age Mean
65.2
63.42
65.81
(SD)
(7.9)
(7.90)
(7.77)
46-84
46-79
47-84
Range Marital Status Single
16 (7.4%)
8 (9.1%)
7 (7.9%)
118 (54.6%)
56 (63.6%)
53 (59.6%)
Divorced, separated
25 (11.6%)
13 (14.8%)
11 (12.4%)
Widowed
32 (14.8%)
11 (12.5%)
18 (20.2%)
Full time
16 (7.4%)
12 (13.6%)
4 (4.5%)
Part time
2 (2.2%)
Partnership, marriage
Employment Status 12 (5.6%)
10 (11.4%)
Unemployed
2 (0.9%)
1 (1.1%)
1 (1.1%)
Homemaker
28 (13.0%)
13 (14.8%)
12 (13.5%)
Retired
130 (60.2%)
50 (56.8%)
70 (78.7%)
Other
3 (1.4%)
2 (2.3%)
—
27 (12.%)
15 (17.0%)
11 (12.4%
Mean
30.4
27.26
32.8
(SD)
(20.7)
(17.87)
(22.67)
0.6-89.5
2.5-66.53
0.66-89.50
140 (64.8%)
56 (63.6%)
61 (68.5%)
70 (32.4%)
32 (36.4%)
26 (29.2%) 12 (13.5%)
Smoking Yes Duration of Adjuvant Endocrine Therapy (mo)
Range Primary Surgical Treatment Breast conserving surgerya Mastectomya Chemotherapy Yes
34 (15.7%)
14 (15.9%)
Adjuvant
21 (9.7%)
8 (9.1%)
6 (6.7%)
Neoadjuvant
13 (6.0%)
(6.8%)
6 (6.7%)
Radiotherapy Yes
151 (69.9%)
63 (71.6%)
63 (70.8%)
41 (19.0%)
15 (17.0%)
20 (22.5%)
26.2
22.51
29.57
Antidepressants Yes BMI Mean (SD)
(4.4)
(1.90)
(3.40)
Range
15.2-43.7
15.19-25.39
25.51-43.71
Median
25.5
Abbreviation: BMI ¼ body mass index. a With or without reconstruction.
protein, creatinine, urea, and estimated glomerular filtration rate in the regression model based on their statistically significant correlation with anastrozole serum concentrations on univariate analysis.
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BMI and Anastrozole Plasma Levels Figure 1 Correlation of Anastrozole Serum Concentrations and Body Mass Index
Abbreviations: BMI ¼ body mass index.
In this multivariate model, this study determined the predictive value of BMI (standardized b ¼ 0.205; t ¼ 2.478; P ¼ .014), total protein (b ¼ 0.193; t ¼ 2.367; P ¼ .019), and urea (b ¼ 0.183; t ¼ 2.214; P ¼ .029) on anastrozole serum concentrations.
Discussion AIs have been highly effective for the prevention of breast cancer recurrence, thereby greatly contributing to the improved outcome of breast cancer achieved in recent years in postmenopausal patients. However, recent findings of reduced anastrozole treatment efficacy in patients with elevated adiposity1,3 have led to questioning of standard dose recommendations in terms of an adequate suppression of estrogen serum levels in women with increased BMI. Yet not all findings support the use of BMI as a predictor for worse prognosis for patients treated with an AI compared with tamoxifen.14 It is possible that this effect is confined to the AI anastrozole only. Although the mechanism
Table 2 Anastrozole Plasma Concentration per Body Mass Index Group Body Mass Index Groups
30 (n [ 26)
Anastrozole Plasma Levels (ng/mL)
4
-
Mean
31.2
32.6
38.3
40.1
(SD)
(5.8)
(12.3)
(14.2)
(13.2)
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potentially mediating any difference in adjuvant efficacy favoring letrozole over anastrozole is unknown, biologic plausibility is afforded by greater influence of letrozole on circulating reproductive hormone levels.15 To date, targeted information on the association of BMI and anastrozole pharmacokinetics is scarce. This study sought to provide more detailed knowledge regarding the association of BMI and anastrozole plasma concentration in postmenopausal patients with breast cancer. By focusing on pharmacokinetic aspects of anastrozole, the authors aimed to contribute to the understanding of the effect of obesity on anastrozole treatment efficacy. The study found that BMI is a vital factor in anastrozole metabolism, as indicated by anastrozole plasma concentration and FSH plasma concentration, which was used as a surrogate marker for estrogenic activity. In fact, significantly higher anastrozole steady-state plasma concentrations were observed in women with obesity compared with women with a normal BMI. Physiologic changes related to obesity have been reported to lead to alterations in the distribution, binding, and elimination of many drugs.16,17 The present results may indicate that an elevated BMI is related to a significantly altered volume of distribution of this drug, a reduced elimination of it, or both. One possible explanation is that adipose tissue not only represents a principal source of estrogens but also may act as a reservoir for drugs that inhibit their production, such as anastrozole. During the regular oral intake, anastrozole is well absorbed in the bloodstream and is extensively distributed in the adipose tissue; it then accumulates and slowly redistributes in the bloodstream. Accordingly, an increased overall volume of adipose tissue may be associated with a higher capacity to store anastrozole.
Michael Hubalek et al Figure 2 Mean Serum Follicle Stimulating Hormone (FSH) Levels in Women With Breast Cancer With and Without Excess Body Weight
Abbreviations: BMI ¼ body mass index; FSH ¼ follicle stimulating hormone.
This storage may lead to altered elimination kinetics and elevated steady-state plasma concentrations. However, according to current evidence, the causal associations are unclear and definitely need further elucidation in subsequent research. The authors further hypothesized other, BMI-related physiologic mechanisms that may contribute to altered anastrozole pharmacokinetics in women with obesity. Because the primary route of anastrozole elimination is hepatic/fecal (85%), with less than 10% excreted in urine, the effect of hepatic and renal function on anastrozole plasma concentration was investigated. Although none of the indicators for hepatic function was associated with anastrozole plasma level, evidence was found for the predictive value of renal function, indicated by a positive correlation between anastrozole concentration and urea concentration regarding anastrozole serum concentration. Impairments in renal function might therefore serve as a moderating variable in anastrozole pharmacokinetics. In view of this positive correlation of BMI and anastrozole serum concentration under consideration of hepatic and renal function, BMI can most certainly be excluded as a cause of low serum anastrozole concentrations, which has been assumed as a reason for worse prognosis.1 Additionally, this study found opposed effects on FSH serum levels in women with obesity, indicating an increased estrogenic activity in these patients despite higher levels of anastrozole. This observation is what most probably accounts for the worse prognosis in women with excess weight, which has been observed in various studies.1,3,10,18 It can also be concluded that the increased total-body aromatization of women with excess weight may, at least in part, be compensated by increased plasma concentrations of anastrozole.10
Finally, it seems likely that other aspects, besides pharmacokinetic factors, also influenced by obesity, may be responsible for the worse prognosis in women with excess weight. Another notable finding herein is the marked interindividual variability of anastrozole steady-state concentrations in this standard after-care sample (median, 34.7 ng/mL; range, 0/5.4-86.5). These results are of notable concordance with the data of Ingle et al19 (median, 32.2; range, 0-98.8), who investigated anastrozole metabolism and pharmacokinetics in a comparable cohort, indicating substantial variability of drug concentrations, as well as variability of change in estradiol concentrations, after the application of the endocrine agent. According to their findings, Ingle et al clearly suggest confounding factors, such as BMI or genetic variation, to make up for these distinct interindividual differences. Thus, they strongly question the “one size fits all” approach of anastrozole dosing and underline the need for patient-specific pharmacokinetic/ genomic information to target anastrozole treatment. The present results strengthen these considerations. To date, investigations devoted to the question of who benefits best might predominantly imply that the identification of a defined range of anastrozole serum concentration is required to achieve therapeutic efficacy rather than focusing on indirect parameters for efficacy evaluation, such as BMI or genetic variations. In fact, despite the extensive evidence on the effect of standard dosing of anastrozole (1 mg is known to lead to 80% estradiol suppression),20 knowledge on what should be the appropriate value of anastrozole serum concentrations is lacking. The present study might also indicate that the available AIs (anastrozole, letrozole, and exemestane) do not have equivalent activity against breast cancer in the
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BMI and Anastrozole Plasma Levels adjuvant setting. Especially, the observation that women with obesity have lower FSH levels and therefore exhibit a higher estrogenic activity would indicate less efficacy of anastrozole in the adjuvant setting. Certainly, using gonadotropin levels as a surrogate marker for anastrozole serum levels might be considered to determine a range of serum concentrations required to achieve therapeutic efficacy. The authors are addressing this issue in ongoing studies. One major limitation of this study is the lack of estradiol levels. However, Pfeiler et al10 found that FSH is a simple and easy-tomeasure surrogate marker for estradiol levels. The present authors acknowledge that this study is limited by its cross-sectional design, not allowing for longitudinal follow-up of women and involving a lack of information on changes of both BMI and anastrozole plasma concentrations over time. Further knowledge on inter- and intraindividual variations of anastrozole plasma concentrations associated with BMI could improve the understanding of this subject. Nonetheless, the strengths of this study include a large sample size and high medication adherence rates, as confirmed by very few concentrations below the LLOQ (1.8%). Moreover, the mean steady-state concentrations found in this cohort (mean, 37.1 ng/mL; SD, 15.1) strikingly correspond to mean concentrations observed in a treatment arm of the ATAC trial (mean, 37.4; SD, 15.2), which quoted a 100% adherence rate.21
Conclusion In summary, this study found that BMI is a strong predictor of the serum anastrozole concentration. The explanation for this clinically important finding is at present insufficiently understood. However, BMI is also a predictor for higher estrogenic activity as indicated by elevated FSH levels in women with obesity who are undergoing anastrozole treatment. Based on the findings of this study, additional studies elucidating anastrozole pharmacokinetics, its metabolism pathways, and factors influencing concentration in individuals are needed. The interpretation of this study’s data leads to the conclusion that AI dose should not be adjusted according to BMI as hypothesized by various experts in the field. However, further research in this regard is mandatory to clarify the present results on the association of obesity, AI serum levels, and possible therapeutic efficacy.
Clinical Practice Points Recent evidence suggests a reduced efficacy of anastrozole
treatment in women with obesity. It is assumed that BMI-related increased estrogen levels are insufficiently suppressed by standard anastrozole doses. Nonetheless, evidence is lacking on anastrozole metabolism under consideration of the effect of BMI. This is the first study investigating anastrozole pharmacokinetics in correlation with BMI, and it observed significantly higher anastrozole steady-state plasma concentrations in patients with obesity compared with those with a normal BMI. Additionally, a marked interindividual variability of anastrozole steady-state concentrations in this standard after-care sample was found.
6
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The predictive value of BMI for serum anastrozole concentration
has been confirmed in this study. Nonetheless, the explanation for this clinically important finding is at present insufficiently understood. At this point, it is not recommended to adjust AI dose recommendations according to BMI. Further research in this regard is required to clarify the association of obesity, AI serum levels, and treatment efficacy.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Pfeiler G, Königsberg R, Fesl C, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol 2011; 29:2653-9. 2. Goodwin PJ. Commentary on: “Effect of obesity on survival in women with breast cancer: systematic review and meta-analysis” (Melinda Protani, Michael Coory, Jennifer H. Martin). Breast Cancer Res Treat 2010; 123:637-40. 3. Sestak I, Distler W, Forbes JF, et al. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J Clin Oncol 2010; 28:3411-5. 4. Ewertz M, Jensen MB, Gunnarsdóttir K, et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol 2011; 29:25-31. 5. Berclaz G, Li S, Price KN, et al. Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann Oncol 2004; 15:875-84. 6. Sendur MA, Aksoy S, Zengin N, Altundag K. Efficacy of adjuvant aromatase inhibitor in hormone receptor-positive postmenopausal breast cancer patients according to the body mass index. Br J Cancer 2012; 107:1815-9. 7. Ligibel JA, Winer EP. Aromatase inhibition in obese women: how much is enough? J Clin Oncol 2012; 30:2940-2. 8. Michaud LB, Buzdar AU, Rubin S, et al. The efficacy of anastrozole is not dependent upon body mass index (BMI) in postmenopausal women with advanced breast cancer (BC). Proc Am Soc Clin Oncol 2002; 21:55a. 9. Schmid P, Possinger K, Bohm R, et al. Body mass index as predictive parameter for response and time to progression (TTP) in advanced breast cancer patients treated with letrozole or megestrol acetate. Proc Am Soc Clin Oncol 2000; 19:103a. 10. Pfeiler G, Konigsberg R, Hadji P, et al. Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer. Br J Cancer 2013; 109:1522-7. 11. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41. 12. Beer B, Schubert B, Oberguggenberger A, et al. Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study. Anal Bioanal Chem 2010; 398: 1791-800. 13. World Health Organization Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004; 363:157-63. 14. Goodwin PJ. Obesity and endocrine therapy: host factors and breast cancer outcome. Breast 2013; 22(suppl 2):S44-7. 15. Chlebowski RT. Adjuvant aromatase inhibitor options in overweight and obese postmenopausal women with breast cancer. Breast J 2013; 19:552-4. 16. Adams JP, Murphy PG. Obesity in anaesthesia and intensive care. Br J Anaesth 2000; 85:91-108. 17. Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999; 88:1-7. 18. Gnant M, Pfeiler G, Stoger H, et al. The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: an analysis of the randomised ABCSG-6a trial. Br J Cancer 2013; 109:589-96. 19. Ingle JN, Buzdar AU, Schaid DJ, et al. Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer. Cancer Res 2010; 70: 3278-86. 20. Arimidex: Non-Steroidal Aromatase Inhibitor [product monograph]. AstraZeneca; 2011. 21. Dowsett M, Cuzick J, Howell A, et al. Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the ’Arimidex and tamoxifen alone or in combination’ (ATAC) trial. Br J Cancer 2001; 85: 317-24.
Does Obesity Interfere With Anastrozole Treatment? Positive Association Between Body Mass Index and Anastrozole Plasma Levels Michael Hubalek,1 Anne Oberguggenberger,2 Beate Beer,3 Verena Meraner,2 Monika Sztankay,2 Herbert Oberacher,3 Birthe Schubert,3 Ludwig Wildt,4 Beata Seeber,4 Johannes Giesinger,2 Georg Kemmler,2 Bernhard Holzner,2 Barbara Sperner-Unterweger2 Abstract Previous research suggests that anastrozole treatment efficacy is associated with body mass index (BMI). This study investigated pharmacokinetic aspects of anastrozole and BMI in 235 patients with breast cancer and found BMI to be a vital component in anastrozole metabolism, as indicated by anastrozole plasma concentration. Nevertheless, women with obesity still displayed higher estrogenic activity compared with those without obesity. Introduction: The efficacy of adjuvant endocrine treatment with aromatase inhibitors (AIs), inhibiting the conversion of androgens to estrogen in adipose tissue, might depend on the overall volume of adipose tissue. However, little evidence is available regarding the pharmacokinetic behavior of AIs in women with obesity. The aim of this study was to investigate the interaction between body mass index (BMI) and anastrozole treatment as well as estrogenic activity. Patients and Methods: A total of 216 postmenopausal patients with early-stage breast cancer who were receiving AI treatment with anastrozole constituted the final sample included in the analysis. During a regular 3-month after-care check-up, sociodemographic and clinical data and BMI were assessed. Blood samples were collected during routine blood testing. Measurement of AI plasma levels was performed by liquid chromatographyetandem mass spectrometry. Follicle stimulating hormone (FSH) and estradiol were measured within the routine blood examination. Results: A median anastrozole plasma concentration of 34.7 ng/mL (mean, 37.4), with a large interindividual variability, was observed (SD, 15.1; range, 5.4-86.5). After age adjustment, it was found that anastrozole plasma concentrations significantly increased with BMI (r ¼ 0.241; P ¼ .001). Anastrozole serum concentrations in women with obesity (BMI 30) exceeded those of women with normal weight (BMI 25) by 25%. Women with excess weight had lower mean FSH levels, indicating higher estrogenic activity, compared with women with normal weight. Conclusion: This study indicates that BMI is a vital factor in anastrozole metabolism, as measured by anastrozole plasma concentration and FSH levels. Further research is mandatory to clarify results on the association of obesity and AI treatment efficacy to allow adapting AI treatment accordingly. Clinical Breast Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Anastrozole treatment efficacy, Aromatase inhibitor, Aromatase inhibitor, Association of BMI and AI plasma concentrations, Breast cancer, BMI, Levels
M. Hubalek and A. Oberguggenberger contributed equally to this work as first authors. 1
Department of Obstetrics and Gynecology 2 Department of Psychiatry and Psychotherapy 3 Institute of Legal Medicine and Core Facility Metabolomics 4 Department of Gynecological Endocrinology and Reproductive Medicine Innsbruck Medical University, Innsbruck, Austria Submitted: Sep 24, 2013; Revised: Dec 23, 2013; Accepted: Dec 23, 2013 Address for correspondence: Michael Hubalek, Department of Gynecology and Obstetrics, Innsbruck Medical University, Anichstraße 35, 6020 Innsbruck, Austria E-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.12.008
Introduction Recent findings regarding the effect of obesity on the efficacy of adjuvant endocrine treatment with aromatase inhibitors (AIs) for early-stage breast cancer have added to the debate on whether women with obesity benefit less from AI treatment in terms of disease-free survival and overall survival.1 It is a well-known fact that obesity increases total-body aromatization and leads to increased estrogen levels in women with obesity compared with age-matched women with normal or low weight.2 The question has been raised
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BMI and Anastrozole Plasma Levels if standardized dosing of anastrozole might be insufficient to adequately suppress heightened aromatization related to obesity. Overall, little evidence in this regard has been reported, and the available studies yielded inconclusive results.1,3-6 Although initial findings7-9 suggested no association of body mass index (BMI) and AI efficacy in patients with metastatic disease, results from the ATAC trial (Arimidex and Tamoxifen Alone or in Combination) indicate lower efficacy of anastrozole treatment in women with obesity (BMI > 30) in terms of time to recurrence.3 This is in accordance with the findings of Ewertz et al,4 who investigated the efficacy of AIs in correlation with weight and found a survival benefit for women with a BMI < 30 after 10 years of follow-up. No group differences were found for the first 10 years of follow-up. Finally, Pfeiler et al1 observed a 60% relative increase in risk for disease recurrence as well as a 2-fold increase in the risk for death in patients with excess weight compared with those with normal weight receiving anastrozole therapy in the ABCSG 12 trial (Austrian Breast and Colorectal Cancer Study Group trial 12). The authors strongly suggest that incomplete estrogen serum level suppression through inadequate anastrozole dosing explains these findings, and they assume an AI dose adjustment according to body weight to be essential for the optimization of treatment efficacy. Nonetheless, evidence is lacking about patterns of anastrozole pharmacokinetics in correlation with obesity. To the best of the authors’ knowledge, there is no observational study on AI plasma concentrations related to BMI available that illustrates altered anastrozole elimination in women with obesity. Additionally, the authors evaluated follicle stimulating hormone (FSH) levels as a surrogate marker for estrogenic activity.10 The purpose of this study was to contribute to the clarification of the interaction of anastrozole treatment and obesity. Thus, the following research question was addressed: Are anastrozole plasma concentrations associated with BMI? Ethical approval for this project was obtained from the Ethics Committee of the Innsbruck Medical University.
Patients and Methods Sample This cross-sectional study was performed at the outpatient unit of the Department of Gynecology and Obstetrics. Patients with breast cancer were found eligible when meeting the following inclusion criteria: a diagnosis of breast cancer stage I to III; adjuvant endocrine therapy with anastrozole for at least 2 weeks after primary surgery for breast cancer; postmenopausal state; maximum age of 85 years; no recurrent or metastatic disease; no overt cognitive impairment; no previous treatment with antihormonal medication; and written informed consent.
Physical Examination Data Weight (to the nearest 0.5 kg) and height (to the nearest 0.5 cm) were measured while the patient underwent routine follow-up examination for breast cancer. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters (kg/m2). Patients were assigned, according to their BMI, to 1 of 3 groups: those with normal weight (BMI 25), those who were overweight (BMI > 25 and 30), and those with obesity (BMI > 30).
Laboratory Data Blood samples were collected at one of the patient’s routine follow-up visits (which are done every 3 months) within the course of endocrine treatment (ranging from 3 to 89 months after treatment initiation). Mean treatment duration was 30.6 months. Liver function parameters and kidney function parameters were measured by standard and quality-controlled procedures. Hepatic function was indicated by gamma glutamyl transferase (gGT), alanine aminotransferase, aspartate aminotransferase, bilirubin, lactate dehydrogenase, and albumin; renal function was investigated by creatinine and urea. Creatinine clearance was estimated by using the Cockcroft-Gault formula.11 Additionally, estradiol and FSH levels were measured as part of the routine laboratory examination of the central laboratory, with kits for electrochemiluminescence immunoassays (Roche Diagnostics) on an automated analyzer (Modular E170 Immunology Analyzer; Roche Analytics). The detection limit for estradiol was 12 pg/mL at the central laboratory. However, almost all measured sera exhibited estradiol levels under the detection limit. AI plasma concentrations were determined by a fully validated liquid chromatographyetandem mass spectrometry (LC-MS/MS) method published elsewhere.12 To prepare the collected samples for LC-MS/MS analysis, 1 mL plasma was treated with a solid phase extraction procedure using a cation mixed-mode polymeric sorbent phase (Strata-X-C cartridges; Phenomenex, Torrance, CA). Chromatographic separation was accomplished on a reversed-phase column (200 mm 0.5 mm, Eurospher C18, 5 mm; Knauer, Berlin, Germany) by using a gradient of acetone in an aqueous hexafluorobutyric acid solution. Tandem mass spectrometric detection was performed on a quadrupole-quadrupole-linear ion trap instrument (3200 Q Trap; Applied Biosystems/Life Technologies). The mass spectrometer was operated in the positive ion mode with a TurboIonSpray source (Applied Biosystems/Life Technologies). Multiple reaction monitoring was performed using the precursor-to-product ion transitions m/z 294.2/225.2 (quantitative) and 294.2/210.1 (qualitative) for anastrozole, 286.2/217.1 (quantitative) and 286.2/190.2 (qualitative) for letrozole, and 249.3/193.2 (quantitative) and 249.3/175.2 (qualitative) for the internal standard bunitrolol.
Procedure
2
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Eligible patients were identified by a search of the medical records. Eligible patients were approached during a standard after-care check-up at the outpatient unit of the Department of Gynecology and Obstetrics. These patients were informed about the study, and each provided written informed consent. Blood samples were collected as part of routine blood testing (as described later). Plasma was then stored at 80 C until the analysis of AI levels. Routine parameters were measured immediately.
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Statistical Analysis Characteristics of the study population were grouped according to low BMI ( 25) and high BMI (> 25) and were reported as percentages, ranges, means, and standard deviations. The Student t test, Mann-Whitney U test, and c2 test were used to compare differences between groups, as appropriate. Partial correlations were used for determining the association of anastrozole plasma levels with BMI, correcting for age. Univariate correlation analyses
Michael Hubalek et al between anastrozole levels and liver function parameters and kidney function parameters were performed with Spearman and Pearson correlation, as appropriate. Patients with values less than the lower limit of quantitation (c < LLOQ) were classified as nonadherent and were excluded from the analysis. The effect of hepatic and renal function on anastrozole levels was further investigated by means of linear regression analysis.
Results Patient Characteristics Between June 2009 and October 2010, 235 patients were included in the study. For 15 patients, no blood samples could be gathered (owing to logistic reasons), and 4 patients were excluded from the analysis due to anastrozole plasma concentrations below the LLOQ. A total of 216 patients with early-stage breast cancer and receiving anastrozole therapy for a mean duration of 30.4 months (SD, 20.4) constituted the final sample included for the analysis. Data on BMI were available for only 177 patients, owing to logistic reasons in the follow-up setting. The most frequent histopathologic cancer type in this study sample was invasive ductal carcinoma (76.4%) and grade II carcinoma (73.1%). Patients were aged between 46 and 84 years, with a mean patient age of 65.2 (SD, 7.9). A median BMI of 26.1 (SD, 4.5) was observed; 2 (0.9%) patients were underweight, and 26 (12%) were obese, according to World Health Organization definitions.13 Further details are presented in Table 1. Patients with normal weight (BMI 25) were further compared with patients with excess weight (BMI > 25) regarding their sociodemographic and clinical data. No significant group differences were found for any of the collected patient characteristics.
Association of BMI and AI Plasma Concentrations A median anastrozole plasma concentration of 34.7 ng/mL (mean, 37.4; SD, 15.1) was observed. A range of 5.4 to 86.5 ng/mL for AI plasma levels showed a large interindividual variability. After correcting for age, anastrozole plasma concentration significantly increased as BMI increased (r ¼ 0.241; P ¼ .001) (Fig. 1; Table 2).
Effect of BMI on Serum FSH Levels Additionally, the effect of BMI was also indicated by a significant negative association of BMI and FSH (r ¼ 0.289; P ¼ .005), which was evident also after correcting for anastrozole plasma concentration using partial correlation (r ¼ 0.265; P ¼ .011). The mean FSH levels (which can be seen as a surrogate marker for estrogenic activity) of women with obesity were significantly lower than the levels of women without obesity, indicating a higher estrogenic activity in the former (Fig. 2). Owing to the detection limit of the routine assay used to determine estradiol levels, estradiol levels adequate for the investigation of the subject addressed herein could not be obtained.
Effect of Hepatic and Renal Function on AI Serum Concentration The effect of hepatic and renal function on AI serum concentration was investigated using regression analysis. Independent variables included BMI, gGT, alanine aminotransferase, aspartate aminotransferase, bilirubin, lactate dehydrogenase, albumin, total
Table 1 Sociodemographic and Clinical Data All (n [ 216)
BMI £25 (n [ 88)
BMI >25 (n [ 89)
Frequency (%) Frequency (%) Frequency (%) Age Mean
65.2
63.42
65.81
(SD)
(7.9)
(7.90)
(7.77)
46-84
46-79
47-84
Range Marital Status Single
16 (7.4%)
8 (9.1%)
7 (7.9%)
118 (54.6%)
56 (63.6%)
53 (59.6%)
Divorced, separated
25 (11.6%)
13 (14.8%)
11 (12.4%)
Widowed
32 (14.8%)
11 (12.5%)
18 (20.2%)
Full time
16 (7.4%)
12 (13.6%)
4 (4.5%)
Part time
2 (2.2%)
Partnership, marriage
Employment Status 12 (5.6%)
10 (11.4%)
Unemployed
2 (0.9%)
1 (1.1%)
1 (1.1%)
Homemaker
28 (13.0%)
13 (14.8%)
12 (13.5%)
Retired
130 (60.2%)
50 (56.8%)
70 (78.7%)
Other
3 (1.4%)
2 (2.3%)
—
27 (12.%)
15 (17.0%)
11 (12.4%
Mean
30.4
27.26
32.8
(SD)
(20.7)
(17.87)
(22.67)
0.6-89.5
2.5-66.53
0.66-89.50
140 (64.8%)
56 (63.6%)
61 (68.5%)
70 (32.4%)
32 (36.4%)
26 (29.2%) 12 (13.5%)
Smoking Yes Duration of Adjuvant Endocrine Therapy (mo)
Range Primary Surgical Treatment Breast conserving surgerya Mastectomya Chemotherapy Yes
34 (15.7%)
14 (15.9%)
Adjuvant
21 (9.7%)
8 (9.1%)
6 (6.7%)
Neoadjuvant
13 (6.0%)
(6.8%)
6 (6.7%)
Radiotherapy Yes
151 (69.9%)
63 (71.6%)
63 (70.8%)
41 (19.0%)
15 (17.0%)
20 (22.5%)
26.2
22.51
29.57
Antidepressants Yes BMI Mean (SD)
(4.4)
(1.90)
(3.40)
Range
15.2-43.7
15.19-25.39
25.51-43.71
Median
25.5
Abbreviation: BMI ¼ body mass index. a With or without reconstruction.
protein, creatinine, urea, and estimated glomerular filtration rate in the regression model based on their statistically significant correlation with anastrozole serum concentrations on univariate analysis.
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BMI and Anastrozole Plasma Levels Figure 1 Correlation of Anastrozole Serum Concentrations and Body Mass Index
Abbreviations: BMI ¼ body mass index.
In this multivariate model, this study determined the predictive value of BMI (standardized b ¼ 0.205; t ¼ 2.478; P ¼ .014), total protein (b ¼ 0.193; t ¼ 2.367; P ¼ .019), and urea (b ¼ 0.183; t ¼ 2.214; P ¼ .029) on anastrozole serum concentrations.
Discussion AIs have been highly effective for the prevention of breast cancer recurrence, thereby greatly contributing to the improved outcome of breast cancer achieved in recent years in postmenopausal patients. However, recent findings of reduced anastrozole treatment efficacy in patients with elevated adiposity1,3 have led to questioning of standard dose recommendations in terms of an adequate suppression of estrogen serum levels in women with increased BMI. Yet not all findings support the use of BMI as a predictor for worse prognosis for patients treated with an AI compared with tamoxifen.14 It is possible that this effect is confined to the AI anastrozole only. Although the mechanism
Table 2 Anastrozole Plasma Concentration per Body Mass Index Group Body Mass Index Groups
30 (n [ 26)
Anastrozole Plasma Levels (ng/mL)
4
-
Mean
31.2
32.6
38.3
40.1
(SD)
(5.8)
(12.3)
(14.2)
(13.2)
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potentially mediating any difference in adjuvant efficacy favoring letrozole over anastrozole is unknown, biologic plausibility is afforded by greater influence of letrozole on circulating reproductive hormone levels.15 To date, targeted information on the association of BMI and anastrozole pharmacokinetics is scarce. This study sought to provide more detailed knowledge regarding the association of BMI and anastrozole plasma concentration in postmenopausal patients with breast cancer. By focusing on pharmacokinetic aspects of anastrozole, the authors aimed to contribute to the understanding of the effect of obesity on anastrozole treatment efficacy. The study found that BMI is a vital factor in anastrozole metabolism, as indicated by anastrozole plasma concentration and FSH plasma concentration, which was used as a surrogate marker for estrogenic activity. In fact, significantly higher anastrozole steady-state plasma concentrations were observed in women with obesity compared with women with a normal BMI. Physiologic changes related to obesity have been reported to lead to alterations in the distribution, binding, and elimination of many drugs.16,17 The present results may indicate that an elevated BMI is related to a significantly altered volume of distribution of this drug, a reduced elimination of it, or both. One possible explanation is that adipose tissue not only represents a principal source of estrogens but also may act as a reservoir for drugs that inhibit their production, such as anastrozole. During the regular oral intake, anastrozole is well absorbed in the bloodstream and is extensively distributed in the adipose tissue; it then accumulates and slowly redistributes in the bloodstream. Accordingly, an increased overall volume of adipose tissue may be associated with a higher capacity to store anastrozole.
Michael Hubalek et al Figure 2 Mean Serum Follicle Stimulating Hormone (FSH) Levels in Women With Breast Cancer With and Without Excess Body Weight
Abbreviations: BMI ¼ body mass index; FSH ¼ follicle stimulating hormone.
This storage may lead to altered elimination kinetics and elevated steady-state plasma concentrations. However, according to current evidence, the causal associations are unclear and definitely need further elucidation in subsequent research. The authors further hypothesized other, BMI-related physiologic mechanisms that may contribute to altered anastrozole pharmacokinetics in women with obesity. Because the primary route of anastrozole elimination is hepatic/fecal (85%), with less than 10% excreted in urine, the effect of hepatic and renal function on anastrozole plasma concentration was investigated. Although none of the indicators for hepatic function was associated with anastrozole plasma level, evidence was found for the predictive value of renal function, indicated by a positive correlation between anastrozole concentration and urea concentration regarding anastrozole serum concentration. Impairments in renal function might therefore serve as a moderating variable in anastrozole pharmacokinetics. In view of this positive correlation of BMI and anastrozole serum concentration under consideration of hepatic and renal function, BMI can most certainly be excluded as a cause of low serum anastrozole concentrations, which has been assumed as a reason for worse prognosis.1 Additionally, this study found opposed effects on FSH serum levels in women with obesity, indicating an increased estrogenic activity in these patients despite higher levels of anastrozole. This observation is what most probably accounts for the worse prognosis in women with excess weight, which has been observed in various studies.1,3,10,18 It can also be concluded that the increased total-body aromatization of women with excess weight may, at least in part, be compensated by increased plasma concentrations of anastrozole.10
Finally, it seems likely that other aspects, besides pharmacokinetic factors, also influenced by obesity, may be responsible for the worse prognosis in women with excess weight. Another notable finding herein is the marked interindividual variability of anastrozole steady-state concentrations in this standard after-care sample (median, 34.7 ng/mL; range, 0/5.4-86.5). These results are of notable concordance with the data of Ingle et al19 (median, 32.2; range, 0-98.8), who investigated anastrozole metabolism and pharmacokinetics in a comparable cohort, indicating substantial variability of drug concentrations, as well as variability of change in estradiol concentrations, after the application of the endocrine agent. According to their findings, Ingle et al clearly suggest confounding factors, such as BMI or genetic variation, to make up for these distinct interindividual differences. Thus, they strongly question the “one size fits all” approach of anastrozole dosing and underline the need for patient-specific pharmacokinetic/ genomic information to target anastrozole treatment. The present results strengthen these considerations. To date, investigations devoted to the question of who benefits best might predominantly imply that the identification of a defined range of anastrozole serum concentration is required to achieve therapeutic efficacy rather than focusing on indirect parameters for efficacy evaluation, such as BMI or genetic variations. In fact, despite the extensive evidence on the effect of standard dosing of anastrozole (1 mg is known to lead to 80% estradiol suppression),20 knowledge on what should be the appropriate value of anastrozole serum concentrations is lacking. The present study might also indicate that the available AIs (anastrozole, letrozole, and exemestane) do not have equivalent activity against breast cancer in the
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BMI and Anastrozole Plasma Levels adjuvant setting. Especially, the observation that women with obesity have lower FSH levels and therefore exhibit a higher estrogenic activity would indicate less efficacy of anastrozole in the adjuvant setting. Certainly, using gonadotropin levels as a surrogate marker for anastrozole serum levels might be considered to determine a range of serum concentrations required to achieve therapeutic efficacy. The authors are addressing this issue in ongoing studies. One major limitation of this study is the lack of estradiol levels. However, Pfeiler et al10 found that FSH is a simple and easy-tomeasure surrogate marker for estradiol levels. The present authors acknowledge that this study is limited by its cross-sectional design, not allowing for longitudinal follow-up of women and involving a lack of information on changes of both BMI and anastrozole plasma concentrations over time. Further knowledge on inter- and intraindividual variations of anastrozole plasma concentrations associated with BMI could improve the understanding of this subject. Nonetheless, the strengths of this study include a large sample size and high medication adherence rates, as confirmed by very few concentrations below the LLOQ (1.8%). Moreover, the mean steady-state concentrations found in this cohort (mean, 37.1 ng/mL; SD, 15.1) strikingly correspond to mean concentrations observed in a treatment arm of the ATAC trial (mean, 37.4; SD, 15.2), which quoted a 100% adherence rate.21
Conclusion In summary, this study found that BMI is a strong predictor of the serum anastrozole concentration. The explanation for this clinically important finding is at present insufficiently understood. However, BMI is also a predictor for higher estrogenic activity as indicated by elevated FSH levels in women with obesity who are undergoing anastrozole treatment. Based on the findings of this study, additional studies elucidating anastrozole pharmacokinetics, its metabolism pathways, and factors influencing concentration in individuals are needed. The interpretation of this study’s data leads to the conclusion that AI dose should not be adjusted according to BMI as hypothesized by various experts in the field. However, further research in this regard is mandatory to clarify the present results on the association of obesity, AI serum levels, and possible therapeutic efficacy.
Clinical Practice Points Recent evidence suggests a reduced efficacy of anastrozole
treatment in women with obesity. It is assumed that BMI-related increased estrogen levels are insufficiently suppressed by standard anastrozole doses. Nonetheless, evidence is lacking on anastrozole metabolism under consideration of the effect of BMI. This is the first study investigating anastrozole pharmacokinetics in correlation with BMI, and it observed significantly higher anastrozole steady-state plasma concentrations in patients with obesity compared with those with a normal BMI. Additionally, a marked interindividual variability of anastrozole steady-state concentrations in this standard after-care sample was found.
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The predictive value of BMI for serum anastrozole concentration
has been confirmed in this study. Nonetheless, the explanation for this clinically important finding is at present insufficiently understood. At this point, it is not recommended to adjust AI dose recommendations according to BMI. Further research in this regard is required to clarify the association of obesity, AI serum levels, and treatment efficacy.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Pfeiler G, Königsberg R, Fesl C, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol 2011; 29:2653-9. 2. Goodwin PJ. Commentary on: “Effect of obesity on survival in women with breast cancer: systematic review and meta-analysis” (Melinda Protani, Michael Coory, Jennifer H. Martin). Breast Cancer Res Treat 2010; 123:637-40. 3. Sestak I, Distler W, Forbes JF, et al. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J Clin Oncol 2010; 28:3411-5. 4. Ewertz M, Jensen MB, Gunnarsdóttir K, et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol 2011; 29:25-31. 5. Berclaz G, Li S, Price KN, et al. Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann Oncol 2004; 15:875-84. 6. Sendur MA, Aksoy S, Zengin N, Altundag K. Efficacy of adjuvant aromatase inhibitor in hormone receptor-positive postmenopausal breast cancer patients according to the body mass index. Br J Cancer 2012; 107:1815-9. 7. Ligibel JA, Winer EP. Aromatase inhibition in obese women: how much is enough? J Clin Oncol 2012; 30:2940-2. 8. Michaud LB, Buzdar AU, Rubin S, et al. The efficacy of anastrozole is not dependent upon body mass index (BMI) in postmenopausal women with advanced breast cancer (BC). Proc Am Soc Clin Oncol 2002; 21:55a. 9. Schmid P, Possinger K, Bohm R, et al. Body mass index as predictive parameter for response and time to progression (TTP) in advanced breast cancer patients treated with letrozole or megestrol acetate. Proc Am Soc Clin Oncol 2000; 19:103a. 10. Pfeiler G, Konigsberg R, Hadji P, et al. Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer. Br J Cancer 2013; 109:1522-7. 11. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41. 12. Beer B, Schubert B, Oberguggenberger A, et al. Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study. Anal Bioanal Chem 2010; 398: 1791-800. 13. World Health Organization Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004; 363:157-63. 14. Goodwin PJ. Obesity and endocrine therapy: host factors and breast cancer outcome. Breast 2013; 22(suppl 2):S44-7. 15. Chlebowski RT. Adjuvant aromatase inhibitor options in overweight and obese postmenopausal women with breast cancer. Breast J 2013; 19:552-4. 16. Adams JP, Murphy PG. Obesity in anaesthesia and intensive care. Br J Anaesth 2000; 85:91-108. 17. Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999; 88:1-7. 18. Gnant M, Pfeiler G, Stoger H, et al. The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: an analysis of the randomised ABCSG-6a trial. Br J Cancer 2013; 109:589-96. 19. Ingle JN, Buzdar AU, Schaid DJ, et al. Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer. Cancer Res 2010; 70: 3278-86. 20. Arimidex: Non-Steroidal Aromatase Inhibitor [product monograph]. AstraZeneca; 2011. 21. Dowsett M, Cuzick J, Howell A, et al. Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the ’Arimidex and tamoxifen alone or in combination’ (ATAC) trial. Br J Cancer 2001; 85: 317-24.
