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Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1671-1676 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.9279 Letrozole Suppresses Plasma Estradiol and Estrone Sulphate More Completely Than Anastrozole in Postmenopausal Women With Breast Cancer
From the Edinburgh Breast Unit and Department of Oncology, Western General Hospital, Edinburgh; Academic Department of Biochemistry, Royal Marsden Hospital, London; and the Institute of Cancer Research Clinical Trials and Statistics Unit, Sutton, United Kingdom Corresponding author: J. Michael Dixon, MD, Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom; e-mail: jmd{at}ed.ac.uk
Purpose To compare the effects of anastrozole and letrozole on plasma estradiol (E2) and estrone sulfate (E1S) levels. Patients and Methods Fifty-four postmenopausal women with estrogen receptor–positive breast cancer receiving aromatase inhibitors (AIs) as part of their adjuvant therapy were randomly assigned to receive either 3 months of anastrozole (1 mg) followed by 3 months of letrozole (2.5 mg), both given orally once daily, or 3 months of the opposite sequence. Blood was taken at the same time and the same day of the week from each patient, before and after 3 months of each drug, and plasma levels of E2 and E1S were determined using highly sensitive radioimmunoassays.
Results There were 27 patients in each group. The mean age of the patients was 63 years (range, 49 to 83 years). Baseline E2 levels ranged from 3 pmol/L to 91 pmol/L with a mean of 25.7pmol/L. Only one of 54 (2%) patients had an E2 value Conclusion Letrozole reduces plasma E2 and E1S levels to a significantly greater extent than anastrozole in postmenopausal women taking AIs as part of their adjuvant therapy for hormone receptor–positive breast cancer.
Anastrozole and letrozole are third-generation, highly potent, well-tolerated, nonsteroidal aromatase inhibitors (AIs) used in the treatment of breast cancer.1-3 Past studies have compared the ability of these two drugs to reduce aromatization, and a number of in vitro studies have indicated that letrozole is the more potent AI compared with anastrozole.4-6 The potency of these two nonsteroidal AIs has been studied in the clinical setting. The P039 study by Geisler et al randomly assigned 12 postmenopausal women with metastatic breast cancer to 6 weeks of letrozole followed by 6 weeks of anastrozole or the reverse sequence.7 In this study, residual aromatase activity was detected in 11 of 12 patients following treatment with anastrozole, but in only one of 12 patients following letrozole. Although letrozole was found to suppress estrone and estrone sulfate (E1S) levels to a significantly greater degree than anastrozole, there were no differences in suppression of estradiol (E2) at 6 weeks (84.9% with anastrozole v 87.8% with letrozole).7 Experimental studies in nude mice examined whether the potency of an AI is reflected in its antitumor efficacy. Studies in nude mice models have suggested that letrozole has more potent antitumor efficacy compared with anastrozole.8,9 In the clinical setting, the importance of effectively reducing circulating estrogen levels is supported by the observation that letrozole 2.5 mg daily demonstrated significantly better results in an advanced setting than aminoglutethimide 500 mg daily, with letrozole having the ability to reduce circulating estrogen levels to a significantly greater degree than aminoglutethimide.1,10,11 However, it is currently uncertain as to whether the ability of letrozole to inhibit aromatase to a greater degree than anastrozole is clinically important. Estradiol is the major active hormone binding to the estrogen receptor in breast cancer cells,12 and even in low concentrations (eg, 1 pM-1 nmol/L) it can stimulate tumor growth.13-15 To date, no study has demonstrated that letrozole reduces circulating E2 levels to a greater degree than anastrozole.3 This may be due partly to the availability of assays to measure low concentrations of E2 and to the small numbers of patients included in such studies. We report results from a larger study adequately designed and powered to compare the effect of anastrozole and letrozole on circulating E2 and E1S levels in postmenopausal women with breast cancer receiving these drugs as part of their adjuvant treatment.
Fifty-four postmenopausal women with estrogen receptor–positive breast cancer who were suitable for adjuvant treatment with an AI were enrolled onto this prospective, open-label, randomized study. Postmenopausal status was defined as amenorrhea for 1 year and/or luteinizing hormone with follicular stimulating hormone levels in the postmenopausal range. The mean age of the patients was 63 years (range, 49 to 83 years). Twenty-seven patients were initially treated with letrozole first followed by anastrozole, and 27 were initially treated with anastrozole followed by letrozole (Fig 1). None of the 27 patients receiving immediate anastrozole or letrozole had received prior treatment with chemotherapy. Of the 54 patients, 27 received initial adjuvant therapy with an AI, and 27 received 5 years of adjuvant tamoxifen followed by an AI. Baseline E2 levels varied from 3 to 91 pmol/L, with a mean of 25.7 pmol/L.
Treatment All patients were treated in the Edinburgh Breast Unit (Edinburgh, United Kingdom). Following informed consent, each patient was randomly assigned to receive 3 months of anastrozole (1 mg/d orally) or 2.5 mg of letrozole once daily in a cross-over study (Fig 1).
Study Design
Blood Samples and Hormone Measurement In brief, plasma E2 concentration was measured by radioimmunoassay using a highly specific rabbit antiserum raised against an estradiol-6-carboxymethyloxime-bovine serum albumin conjugate (EIR, Wurenlingen, Switzerland; and Third Generation Estradiol [I125] reagent DSL 39,120; Diagnostic Systems Laboratories Inc, Webster, TX).16 The sensitivity of the assay is defined as 3 pmol/L by calculation from the 95% CIs of the zero standard.16 Values below this limit were estimated by extrapolation of the counter-derived spline-fit of % radioactivity-bound versus log-dose. The lowest standard of the assay was equivalent to 0.74 pmol/L estradiol in the plasma samples. Within-assay variability, assessed in seven assays, with four replicates of a serum pool, gave a mean E2 level of 37 pmol/L and an overall within-assay coefficient of variation of 10%. The between-assay coefficient of variation for the same pool was 12%. Estrone sulfate was measured using radioimmunoassay after conversion to estrone by incubation with sulfatase (Sigma S 9754, 2.0 mg/mL acetate buffer [0.2M, pH 5.0]; Sigma Aldrich Co Ltd, Dorset, United Kingdom) at 37°C for at least 48 hours. The estrone was extracted twice with ether and purified using liquid column chromatography on a Lipidx 5000 (PerkinElmer, Boston, MA) with elution using chloroform:hexane:methanol (50:50:1). The radioimmunoassay used dilutions of a prepared ethanolic standard [I125] estrone reagent from the Diagnostic Systems Laboratories Inc kit DSL-8700 diluted one in two in assay buffer and rabbit antiestrone from the same kit diluted one in four in assay buffer. Standards and samples together with tracer and antiserum were incubated for 2 hours at 25°C. The bound and free fractions were separated using a double antibody system. The estrone and hence the E1S in the serum samples was determined from a calibration curve with correction made to account for recovery as determined from [H3] estrone recovery controls. Within- and between-batch coefficients of variation were 9.9% and 11% at 130 pmol/L (n = 8), and the sensitivity limit was 15 pmol/L.
Statistical Methods
Table 1 presents the pre- and post-treatment values of E2 and E1S, the proportional change, and the ratio of these changes for letrozole and anastrozole. Letrozole (2.5 mg) suppressed E1S and E2 levels to a greater degree than anastrozole (1 mg) in postmenopausal women taking AIs as part of their adjuvant therapy for hormone receptor–positive breast cancer (Fig 2A and 2B). Only one of 54 (2%) patients had an E2 value  3 pmol/L after letrozole, compared with 20 of 54 (37%) patients after anastrozole (P < .001). After extrapolation, the mean E2 level after anastrozole was 2.71 (range, 2.38 to 3.08) pmol/L and after letrozole, it was 1.56 (range, 1.37 to 1.78) pmol/L (Table 1; Fig 2C). Mean residual E2 was 10.1% for anastrozole and 5.9% for letrozole. Residual E1S levels were 4.6% for anastrozole and 2.0% for letrozole (P = .001; data not shown). For E1S, letrozole showed a post-treatment value that was 43% of that demonstrated by anastrozole; in the case of E2, letrozole reduced E2 levels by a further 42% compared with anastrozole (Fig 2C).
Table 2 presents whether the response seen in Table 1 varied if letrozole or anastrozole were given first. There was no evidence of a difference, as the ratio of proportional changes was 60% if letrozole was given initially and 56% if anastrozole was given initially. E2 levels were not significantly different between the two groups (Fig 2D). There was a trend towards a lower ratio of proportional changes in E1S levels in the group initially treated with anastrozole, but this failed to reach statistical significance.
Table 3 presents the comparison of outcome according to previous tamoxifen use. The levels of E2 and E1S were significantly lowered to a greater degree with letrozole than with anastrozole, irrespective of whether patients had received treatment with prior tamoxifen (P < .001; Fig 3A and 3B). The ratios of the proportional changes were similar whether treatment was immediate adjuvant or after 5 years of tamoxifen for both E2 and E1S, indicating that there is no evidence of any subgroup effects.
This study has shown that letrozole (2.5 mg once daily) reduces plasma E2 and E1S levels to a significantly greater degree than anastrozole (1 mg once daily) in postmenopausal women taking AIs as part of their adjuvant therapy for hormone receptor–positive breast cancer. Importantly, greater estrogen suppression was demonstrated in almost all patients irrespective of whether they had received previous tamoxifen. Although another study showed that letrozole suppresses plasma estrone and E1S to a greater degree than anastrozole,7 this is the first analytically designed and adequately powered study to demonstrate significant reductions in circulating E2, the most bioactive estrogen, in patients treated with letrozole compared with those treated with anastrozole. The larger number of patients also enabled the consistency of the difference in suppression of both estrogens to be evaluated. Aromatase inhibition is a long-studied and currently recommended treatment option for postmenopausal women with hormone-sensitive breast cancer. Anastrozole and letrozole are third-generation triazole nonsteroidal AIs that have been previously shown to be highly effective, causing profound suppression of circulating estrogen levels in postmenopausal women.1,2 The P039 study of 12 patients, which had a similar cross-over design to that of this study, demonstrated that letrozole was a more potent suppressor of total body aromatization than anastrozole, but did not show any significant differences in E2, which is thought to be the most important estrogen in breast cancer.7 Previously, one problem has been the technical difficulty of measuring low levels of E2. Although the assay that was used in this study to estimate levels was below its formal sensitivity limit, the assay is robust, and the consistency of the results was reassuring. This approach has previously been used in studies of the breast cancer preventive effect of raloxifene in relation to plasma E2 levels.17 The cross-over design of the study was chosen to remove interpatient variability, also a problem in previous studies. One criticism of the earlier P039 study that used a similar design in only 12 patients was a concern that there would be some carryover effect, because the drugs were given for only 6 weeks each. In reality, carryover even at 6 weeks is minimal because the half-life of both letrozole and anastrozole is between 40 and 50 hours,18,19 and within 4 weeks of stopping anastrozole or letrozole, little drug remains. Twelve weeks is certainly more than adequate to ensure that the results obtained for each drug represent values for that drug and that there is no carryover effect. Consistent with this is the fact that, in our study, letrozole reduced circulating E2 levels to a greater degree than did anastrozole, regardless of sequence. There is evidence of a dose-response relationship between the degree of estrogen suppression and the clinical effectiveness of drugs in breast cancer. Early evidence of the importance of lowering estrogen levels came from the observation that a number of patients who developed progression following castration achieved a further response to suppression of plasma estrogen following adrenalectomy or AI therapy.20,21 There is also evidence of a direct correlation between the effectiveness of an agent and the degree to which it suppresses plasma estrogen. Aminoglutethimide 500 mg/d achieves approximately 85% suppression of plasma estrogen compared with letrozole 2.5 mg, which suppresses estrogen to a level of 99%.7,22 In a large randomized trial comparing the effectiveness of these two agents, there was a significant improvement in overall survival in patients randomized to receive letrozole.10 Three potent third-generation AIs are available, and an important question is whether one is superior to the other two. Letrozole is the most potent agent in vitro.4,5 There are few clinical data directly comparing the effectiveness of letrozole and anastrozole. One second-line study in patients with metastatic disease (N = 713) showed no significant difference between the two drugs in the primary end point of time to progression.23 Although there was a significantly greater response rate with letrozole, when the analysis was restricted to those patients known to be estrogen receptor–positive (N = 340), there was no difference in clinical response rate in this group.23 This was an underpowered study; thus, while the observation of an overall greater response rate is interesting, the fact that the response rates in the estrogen receptor–positive population were identical leads to the conclusion that this study failed to demonstrate any significant difference in outcomes between patients treated second-line with 2.5 mg of letrozole or 1 mg of anastrozole. An important issue that has not been addressed by this study is whether the superiority in terms of its ability to reduce circulating estrogen levels has direct clinical significance. Both anastrozole and letrozole have been compared in the adjuvant setting to tamoxifen and both have been shown to significantly improve disease-free survival compared with tamoxifen.24,25 It is impossible to directly compare these two studies because there were different patient entry criteria. The answer to whether the greater estrogen suppression with letrozole is clinically relevant will have to await the outcome of the current Femara Anastrozole Clinical Evaluation study, a large, phase IIIb trial comparing adjuvant letrozole versus anastrozole in postmenopausal women with node-positive, estrogen receptor–positive breast cancer.26 The group of 54 patients described here is part of a larger study in which quality-of-life adverse effects, bone markers, and lipid profiles have been collected and analyzed. These results, as well as the safety evaluations from the Femara Anastrozole Clinical Evaluation trial, are awaited with 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: David Cameron, Novartis (C), AstraZeneca (C); Mitch Dowsett, AstraZeneca (C), Novartis (C) Stock Ownership: None Honoraria: J. Michael Dixon, AstraZeneca, Novartis; E. Jane Macaskill, AstraZeneca; David Cameron, Pfizer, Novartis, AstraZeneca; Mitch Dowsett, AstraZeneca, Novartis Research Funding: J. Michael Dixon, AstraZeneca, Novartis; Juliette Murray, AstraZeneca, Novartis, Pfizer; Mitch Dowsett, AstraZeneca, Novartis Expert Testimony: None Other Remuneration: None
Conception and design: J. Michael Dixon, David Cameron Financial support: J. Michael Dixon Administrative support: Oliver Young, E. Jane Macaskill Provision of study materials or patients: J. Michael Dixon, Lorna Renshaw, Oliver Young, Juliette Murray, E. Jane Macaskill, Mary McHugh Collection and assembly of data: Lorna Renshaw, Oliver Young, Juliette Murray, E. Jane Macaskill, Mary McHugh, Elizabeth Folkerd, Mitch Dowsett Data analysis and interpretation: Oliver Young, Elizabeth Folkerd, Roger P. A'Hern, Mitch Dowsett Manuscript writing: J. Michael Dixon, Elizabeth Folkerd, David A. Cameron, Mitch Dowsett Final approval of manuscript: J. Michael Dixon, E. Jane Macaskill, David A. Cameron, Mitch Dowsett
We thank all the patients who entered this study.
Supported by an unrestricted educational grant from Novartis. Presented in part at the American Society of Clinical Oncology 2006 Annual Meeting, June 2-6, 2006, Atlanta, GA; in poster format at the European Society for Medical Oncology 31st ESMO Congress,September 29-October 3, 2006, Istanbul, Turkey; and at San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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J Steroid Biochem Mol Biol 79:103-107, 2001[CrossRef][Medline] 6. Bhatnagar AS, Brodie AM, Long BJ, et al: Intracellular aromatase and its relevance to the pharmacological efficacy of aromatase inhibitors. J Steroid Biochem Mol Biol 76:199-202, 2001[CrossRef][Medline] 7. Geisler J, Haynes B, Anker G, et al: Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 20:751-757, 2002 8. Lu Q, Liu Y, Long BJ, et al: The effect of combining aromatase inhibitors with antiestrogens on tumor growth in a nude mouse model for breast cancer. Breast Cancer Res Treat 57:183-192, 1999[CrossRef][Medline] 9. Brodie A, Lu Q, Liu Y, et al: Aromatase inhibitors and their antitumor effects in model systems. Endocr Relat Cancer 6:205-210, 1999[Abstract] 10. Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer: Letrozole International Trial Group (AR/BC3). Ann Oncol 9:639-645, 1998 11. MacNeill FA, Jones AL, Jacobs S, et al: The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer. Br J Cancer 66:692-697, 1992[Medline] 12. Nilsson S, Makela S, Treuter E, et al: Mechanisms of estrogen action. Physiol Rev 81:1535-1565, 2001 13. Chalbos D, Vignon F, Keydar I, et al: Estrogens stimulate cell proliferation and induce secretory proteins in a human breast cancer cell line (T47D). J Clin Endocrinol Metab 55:276-283, 1982 14. Masamura S, Santner SJ, Heitjan DF, et al: Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab 80:2918-2925, 1995 15. Lippert C, Seeger H, Mueck AO: The effect of endogenous estradiol metabolites on the proliferation of human breast cancer cells. Life Sci 72:877-883, 2003[CrossRef][Medline] 16. Dowsett M, Goss PE, Powles TJ, et al: Use of the aromatase inhibitor 4-hydroxyandrostenedione in postmenopausal breast cancer: Optimization of therapeutic dose and route. Cancer Res 47:1957-1961, 1987 17. Cummings SR, Duong T, Kenyon E, et al: Multiple Outcomes of Raloxifene Evaluation (MORE) Trial: Serum estradiol level and risk of breast cancer during treatment with raloxifene. JAMA 287:216-220, 2002 18. Plourde PV, Dyroff M, Dukes M: Arimidex: A potent and selective fourth-generation aromatase inhibitor. Breast Cancer Res Treat 30:103-111, 1994[CrossRef][Medline] 19. Sioufi A, Sandrenan N, Godbillon J, et al: Comparative bioavailability of letrozole under fed and fasting conditions in 12 healthy subjects after a 2.5 mg single oral administration. Biopharm Drug Dispos 18:489-497, 1997[CrossRef][Medline] 20. Huggins C, Dao TL: Adrenalectomy and oophorectomy in treatment of advanced carcinoma of the breast. JAMA 151:1388-1394, 1953[Medline] 21. Samojlik E, Santen RJ, Worgul TJ: Suppression of residual oestrogen production with aminoglutethimide in women following surgical hypophysectomy or adrenalectomy. Clin Endocrinol (Oxf) 20:43-51, 1984[Medline] 22. PE, Geisler J, Johannessen DC, et al: Plasma estrogen suppression with aromatase inhibitors evaluated by a novel, sensitive assay for estrone sulphate. J Steroid Biochem Mol Biol 61:255-260, 1997[CrossRef][Medline] 23. Rose C, Vtoraya O, Pluzanska A, et al: An open randomised trial of second-line endocrine therapy in advanced breast cancer: Comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer 39:2318-2327, 2003[CrossRef][Medline] 24. B, Keshaviah A, Coates AS, et al: on behalf of the Breast International Group (BIG) 1-98 Collaborative Group: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 25. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:600-602, 2005 26. De Boer R, Burris H, Monnier A, et al: On behalf of the H2H trial steering committee: The head to head trial: Letrozole vs anastrozole as adjuvant treatment of postmenopausal patients with node positive breast cancer. J Clin Oncol 24:582s, 2006 (suppl; abstr 10672) Submitted August 8, 2007; accepted December 6, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
