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Originally published as JCO Early Release 10.1200/JCO.2007.13.5319 on December 17 2007 © 2008 American Society of Clinical Oncology. Endocrine Effects of Adjuvant Letrozole + Triptorelin Compared With Tamoxifen + Triptorelin in Premenopausal Patients With Early Breast Cancer
From the National Cancer Institute; and the Department of Medicine and Public Health, Second University of Naples, Naples, Italy Corresponding author: Francesco Perrone, Clinical Trials Unit, National Cancer Institute of Naples, Via Mariano Semmola, 80131, Napoli, Italy; e-mail: francesco.perrone{at}uosc.fondazionepascale.it
Purpose To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study).
Patients and Methods Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin ± zoledronate. Serum 17-β-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Results Median age was 44 years for both groups of patients. Letrozole + triptorelin (± zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Conclusion Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.
The Early Breast Cancer Trialists' Collaborative Group meta-analysis demonstrated the efficacy of adjuvant tamoxifen in reducing the risk of relapse and death in patients with operable breast cancer and with estrogen receptor (ER)–positive tumors.1 These benefits are independent of age, menopausal status, nodal involvement, progesterone receptors, and use of adjuvant chemotherapy. An important change in the adjuvant treatment of postmenopausal patients has occurred in recent years with the publication of the results of the adjuvant trials that used third-generation aromatase inhibitors (AIs).2-5 These trials demonstrated the superiority of AIs to tamoxifen and led to the use of AIs as the preferred adjuvant treatment of postmenopausal women with hormone receptor–positive early breast cancer. In premenopausal patients, AIs can be combined with gonadotropin-releasing hormone (GnRH) agonists that produce postmenopausal-like plasma estrogen concentrations; such combination may be used to treat metastatic breast cancer, but there is no demonstration that it is effective as adjuvant treatment. A strong suppression of estradiol secretion has been demonstrated with the combination of a second-generation AI and a GnRH analog.6,7 Furthermore, a phase I trial that investigated the effects of goserelin + anastrozole in premenopausal women with advanced breast cancer who had progressed after treatment with goserelin + tamoxifen showed a 76% further reduction in estradiol serum levels when tamoxifen was substituted with anastrozole.8 No data are available for the combination of letrozole and triptorelin. The aim of the present study is to compare the endocrine changes that occur in premenopausal patients with early breast cancer after 6 months of treatment with adjuvant letrozole + triptorelin or tamoxifen + triptorelin.
Study Plan In March 2004, we started a single-center, randomized, phase 3 trial of adjuvant endocrine treatment in pre- and postmenopausal patients with hormonal receptor–positive early breast cancer and compared tamoxifen versus letrozole versus letrozole + zoledronic acid (the Hormonal Adjuvant Treatment Bone Effects [HOBOE] study). The primary end point was bone mineral density after 1 year of treatment. In all premenopausal patients, the GnRH-agonist triptorelin was added to the assigned endocrine treatment, and hormonal data were collected prospectively. After the positive results of trials with adjuvant AIs, the protocol was amended in 2005, to allow the switch to aromatase inhibitors after 2 years of tamoxifen in postmenopausal patients. The present analysis was not formally planned but was included in the assessment of safety of treatments among premenopausal patients. The decision to focus the attention on the hormonal effects in premenopausal patients was prompted by the consideration of the paucity of published evidence. Under the assumption that the endocrine effect of zoledronic acid is negligible, data from the two letrozole-based arms — with or without zoledronic acid—have been combined for the present analysis.
Eligibility Criteria
Exclusion criteria were performance status The study was approved by the institutional ethical committee, and all patients provide written informed consent before starting study procedures. Premenopausal patients enrolled up to June 2006 were included in this analysis.
Treatment Plan Women who received adjuvant chemotherapy started their hormonal treatment within 4 to 6 weeks after the end of chemotherapy. Breast irradiation for conservative surgery could be given concomitantly with hormonal treatment. Trastuzumab for patients with human epidermal growth factor receptor 2–positive tumors was registered in Italy after the cutoff date, and no patient considered in this analysis actually received it.
Hormone Assays
Statistical Methods
From March 2004 to June 2006, 234 women were randomly assigned onto the HOBOE study, and 100 of them were premenopausal. Prospectively collected hormonal data were available for 81 women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 to receive letrozole + triptorelin. Mean baseline characteristics of the patients are listed in Table 1. Median age was 44 years for both the groups of patients. Median time since last menses at random assignment was 3 months in the tamoxifen group and 2.6 months in the letrozole group. Twenty-seven patients (90%) in the tamoxifen group and 44 patients (86.3%) in the letrozole group had previously received adjuvant and/or neoadjuvant chemotherapy. All patients, except for one in the letrozole arm who did not actually receive triptorelin, received the assigned treatment for at least 6 months. Baseline median serum hormone levels were similar between the two groups.
In Figure 1, the dynamics of 17-β-estradiol, FSH, and LH between baseline and 6-month assessments are depicted. Two outlying values of FSH and LH were found at 6 months in a patient enrolled in the letrozole arm who was not compliant with triptorelin. It is clear that values consistent with both premenopausal and postmenopausal status were measured at baseline as a consequence of previous adjuvant chemotherapy. After 6 months of treatment (Table 2), letrozole in combination with triptorelin induced a more intense suppression of E2 levels compared with the tamoxifen group (P = .0008; Fig 2, upper left corner). Median FSH serum levels were suppressed in both groups, but this effect was reduced in patients treated with letrozole, who showed significantly higher median FSH serum levels (P < .0001; Fig 2, upper right corner). Median LH serum levels were suppressed in both the groups; a more profound suppression was observed with letrozole compared with tamoxifen (P = .0005; Fig 2, lower left corner). Letrozole also induced a greater suppression of serum cortisol (P < .0001); however, such reduction was not to less than the normal range values and it was never clinically relevant (Fig 2, lower right corner). No significant differences for progesterone, testosterone, androstenedione, DHEA-S, ACTH, and aldosterone between the two groups of patients were observed (Table 2).
The present study shows that premenopausal patients who received letrozole and triptorelin as adjuvant treatment for at least 6 months had a more profound suppression of E2 plasma levels compared with those treated with tamoxifen and triptorelin. Both groups of patients presented a suppression of FSH and LH levels; however, FSH levels were higher and LH levels were lower with letrozole than with tamoxifen. Both of these effects can be explained by the potent suppression of E2 levels produced by letrozole, which removes the negative feedback of E2 on pituitary FSH secretion and the positive feedback of E2 on pituitary LH secretion. Such evidence makes reasonable the hypothesis that the greater efficacy of letrozole versus tamoxifen, already shown in postmenopausal patients,4 could be seen in premenopausal patients, too. Of course, it cannot be ignored that a more profound suppression of E2, which might be therapeutic against breast cancer, should also translate in a greater incidence of long-term adverse effects, such as osteoporosis, impairment of cognitive function and of sexual life, or alteration of lipid metabolism and consequent cardiovascular diseases, that have not been extensively studied yet among premenopausal patients. To our knowledge, this is the largest study to report the endocrine effects of the combined use of GnRH agonists and AIs as treatment of premenopausal patients with breast cancer. It is the first one performed with letrozole and dedicated to the adjuvant setting. In addition, and more importantly, this is the only trial that provide a formal (although unplanned for hormonal effects) comparison with tamoxifen (plus the same GnRH agonist) because of the randomized design. We acknowledge that the population of patients enrolled on our study could not be purely premenopausal because most of them had received adjuvant chemotherapy and were still suffering chemotherapy-induced suppression of ovarian function. Although it is well known that this status may be transient, it has been suggested recently that AIs might even promote the recovery of ovarian function in premenopausal patients with chemotherapy-induced amenorrhoea.9 Such recent data reinforce the pragmatic strategy of the HOBOE study that combines triptorelin with letrozole for all patients who had their last menses within 12 months before random assignment, independent of age and hormonal profile. The few studies that have assessed the hormonal effects of AIs in combination with GnRH agonists in premenopausal patients with breast cancer are listed in Table 3. All were performed in the metastatic setting, and their sample size was small and ranged from six to 35 patients. The studies varied by drugs employed. Goserelin was the analog chosen in four trials,6-8,10 and triptorelin was used only in one study11; formestane (a second-generation AI) was used twice,6,11 as was anastrozole8,10; vorozole (a triazolic AI) was used in one participant.7 The study design also varied. Three studies tested whether hormonal levels were modified by a treatment switch within a planned sequence, that is, by introducing AIs at progression of disease or after a pre-established course of goserelin alone6-8; one study was a simple, phase 2–like study,10 and only one was randomized11 but had a low number of patients in each arm. These studies consistently showed that the addition of AIs to GnRH agonists or their introduction in place of tamoxifen produced a significant further suppression of serum E2 levels. Although FSH and LH were effectively suppressed by GnRH analogs in all of these studies, the effects of AIs on their levels varied. In particular, FSH and LH were unaffected by the addition of formestane to goserelin,6 by the addition of formestane to triptorelin,11 and by the addition of vorozole to goserelin.7 FSH levels increased after the change of tamoxifen with anastrazole (both with goserelin) although they remained within a range of suppression, whereas this treatment change did not affect LH levels.8
Common weaknesses of these studies are the low number of patients and the short follow-up, neither of which allow correlation of the endocrine effects of combined AIs and GnRH agonists to clinical activity. To our knowledge, the only study to investigate this issue is a retrospective analysis by Bajetta et al,12 which suggested the lack of a correlation between estrogen suppression and clinical activity in postmenopausal patients with metastatic breast cancer who were treated with formestane. The endocrine effects of the third-generation AI exemestane given in combination with triptorelin have been evaluated in healthy premenopausal volunteers as well and have been compared with those of placebo + triptorelin. More profound E2 suppression was observed in patients who received triptorelin and exemestane versus triptorelin and placebo; no influence of exemestane on FSH or LH secretion was evident.13 Finally, E2 suppression, with a resultant increase in serum FSH levels, also has been observed with anastrozole as a single agent in 26 healthy volunteers who were premenopausal women.14 An unexpected finding of our study is the significant suppression of cortisol induced by letrozole compared with tamoxifen. We acknowledge that the serum levels of cortisol can be affected by several factors, such as fasting, stress, and timing of cortisol measurement. We did not plan to control such factors prospectively; however, the trial organization and the randomized design let us believe that assays were done in similar conditions (ie, early in the morning after overnight fasting) in both groups. Changes in cortisol levels remained within the normal limits and never produced clinical symptoms, nor was substitutive therapy required. A significant decrease in mean cortisol levels during letrozole treatment was reported previously in two studies. In the first, such a decrease was observed after 2 months of letrozole treatment in 14 postmenopausal patients with metastatic breast cancer, although all values remained within the normal ranges. Moreover, as in our study, no significant changes in aldosterone levels were observed.15 In the second study, which was conducted in 46 postmenopausal women with advanced breast cancer, letrozole showed no significant effect on cortisol or aldosterone levels in the absence of stimulation; however, after 3 months of treatment with letrozole, a significant decrease in peak levels of cortisol and aldosterone after stimulation with ACTH was recorded.16 On the contrary, no such effect has been reported with anastrozole and exemestane.17,18 The effect of letrozole on cortisol secretion may be explained by the activity of the drug on cytochrome P450 enzymes involved in steroid synthesis. Additional and more definitive information regarding the effect of letrozole on cortisol would require the evaluation of cortisol urinary secretion for 24 hours; in addition, comparison of such effects among the different AIs would be of interest. In conclusion, our study demonstrated that letrozole in addition to triptorelin is more effective than tamoxifen for the inhibition of E2 secretion. This result supports the hypothesis that letrozole could be more effective than tamoxifen as adjuvant hormonal treatment for premenopausal patients with endocrine-responsive breast cancer. However, this is only a hypothesis, and it must be tested within large prospective trials; some studies are ongoing, such as the Suppression of Ovarian Function plus the Either Tamoxifen or Exemestane Compared with Tamoxifen Alone (SOFT) and Triptorelin with Either Exemestane or Tamoxifen (TEXT) studies by the International Breast Cancer Group and the trial conducted by the Austrian Breast and Colorectal Cancer Study Group (ABCSG-12). Their results must be presented to verify whether this hypothesis will be confirmed.
The authors indicated no potential conflicts of interest.
Conception and design: Ciro Gallo, Francesco Perrone, Andrea de Matteis Provision of study materials or patients: Emanuela Rossi, Ermelinda De Maio, Francesca Di Rella, Giuseppe Esposito, Adriano Gravina, Vincenzo Labonia, Gabriella Landi, Francesco Nuzzo, Carmen Pacilio, Giuseppe D'Aiuto, Massimiliano D'Aiuto, Massimo Rinaldo, Gerardo Botti, Andrea de Matteis Collection and assembly of data: Emanuela Rossi, Alessandro Morabito, Ermelinda De Maio, Francesca Di Rella, Giuseppe Esposito, Adriano Gravina, Vincenzo Labonia, Gabriella Landi, Francesco Nuzzo, Carmen Pacilio, Maria Carmela Piccirillo, Giuseppe D'Aiuto, Massimiliano D'Aiuto, Massimo Rinaldo, Gerardo Botti, Francesco Perrone, Andrea de Matteis Data analysis and interpretation: Ciro Gallo Manuscript writing: Emanuela Rossi, Alessandro Morabito, Maria Carmela Piccirillo, Francesco Perrone Final approval of manuscript: Emanuela Rossi, Alessandro Morabito, Ermelinda De Maio, Francesca Di Rella, Giuseppe Esposito, Adriano Gravina, Vincenzo Labonia, Gabriella Landi, Francesco Nuzzo, Carmen Pacilio, Maria Carmela Piccirillo, Giuseppe D'Aiuto, Massimiliano D'Aiuto, Massimo Rinaldo, Gerardo Botti, Ciro Gallo, Francesco Perrone, Andrea de Matteis
The following coauthors contributed to the study: The NCI-Naples Breast Cancer Group (Clinical Trials Unit: Francesco Perrone, Alessandro Morabito, Ermelinda De Maio, Massimo Di Maio, Mario Iaccarino, Maria Carmela Piccirillo, Katia Monaco, Jane Bryce, Fabiano Falasconi, Antonia Del Giudice, Roberta D'Aniello; Medical Oncology C: Andrea de Matteis, Francesca Di Rella, Adriano Gravina, Vincenzo Labonia, Gabriella Landi, Francesco Nuzzo, Carmen Pacilio, Emanuela Rossi, Rosa Fiore; Senology: Giuseppe D'Aiuto, Franca Avino, Immacolata Capasso, Massimiliano D'Aiuto, Claudio Longo, Massimo Rinaldo, Renato Thomas; Cell Biology and Preclinical Models Unit: Nicola Normanno, Amelia D'Alessio, Monica Rosaria Maiello, Adele Carotenuto, Gianfranco De Feo, Anna Maria Rachiglio; Nuclear Medicine: Secondo Lastoria, Corradina Caracò, Luigi Aloj; Pathology: Gerardo Botti, Maurizio Di Bonito, Maria Pia Curcio, Franca Formichelli, Franca La Vecchia, Maria Staiano; Pharmacy: Maria Rosaria Salzano, Piera Maiolino; Radiology: Alfredo Siani, Teresa Petrosino, Rosaria Rubulotta, Paolo Vallone, Mauro Matta Ceraso, Antonella Petrillo, Orlando Catalano, Fabio Sandomenico; Radiotherapy: Brunello Morrica). Department of Medicine and Public Health, Second University of Naples: Ciro Gallo, Giuseppe Signoriello, Paolo Chiodini.
We thank Federika Crudele, Giuliana Canzanella, Fiorella Romano, Manuela Florio, and Giovanni de Matteis for data management and Alfonso Savio for informatic support.
Supported in part by Associazione Italiana per la Ricerca sul Cancro. Letrozole and zoledronic acid were supplied at no cost by Novartis, Italy. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Early Breast Cancer Trialist' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 2. 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 365:60-62, 2005[CrossRef][Medline] 3. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two or three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 4. Thürlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 5. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA. 17. J Natl Cancer Inst 97:1262-1271, 2005 6. Stein RC, Dowsett M, Hedley A, et al: The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer. Br J Cancer 62:679-683, 1990[Medline] 7. Dowsett M, Doody D, Miall S, et al: Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer. Breast Cancer Res Treat 56:25-34, 1999[CrossRef][Medline] 8. Forward DP, Cheung KL, Jackson L, et al: Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer. Br J Cancer 90:590-594, 2004[CrossRef][Medline] 9. Smith IE, Dowsett M, Yap YS, et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: Caution and suggested guidelines. J Clin Oncol 24:2444-2447, 2006 10. Carlson RW, Schurman CM, Rivera E, et al: Goserelin plus anastrozole in the treatment of premenopausal hormone receptor positive, recurrent or metastatic breast cancer. J Clin Oncol 25:18S, 2007 (suppl; abstr 1030) 11. Celio L, Martinetti A, Ferrari L, et al: Premenopausal breast cancer patients treated with a gonadotropin releasing hormone analog alone or in combination with an aromatase inhibitor: A comparative endocrine study. Anticancer Res 19(3b):2261-2268, 1999 12. Bajetta E, Zilembo N, Bichisao E, et al: Tumor response and estrogen suppression in breast cancer patients treated with aromatase inhibitors. Ann Oncol 11:1017-1022, 2000 13. Jannuzzo MG, Di Salle E, Spinelli R, et al: Estrogen suppression of 8-week treatment with exemestane combined with triptorelin versus triptorelin alone in healthy premenopausal women. J Clin Oncol 22:14S, 2004 (suppl; abstr 2041) 14. Tredway DR, Buraglio M, Hemsey G, et al: A phase I study of the pharmacokinetics, pharmacodynamics, and safety of single-and multiple-dose anastrozole in healthy, premenopausal female volunteers. Fertil Steril 82:1587-1593, 2004[CrossRef][Medline] 15. Bisagni G, Cocconi G, Scaglione F, et al: Letrozole, a new oral non-steroidal aromatase inhibitor in treating postmenopausal patients with advanced breast cancer: A pilot study. Ann Oncol 7:99-102, 1996 16. Bajetta E, Zilembo N, Dowsett M, et al: Double-blind, randomized, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer 35:208-213, 1999[CrossRef][Medline] 17. 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] 18. Evans TR, di Salle E, Ornati G, et al: Phase I and endocrine study of exemestane (FCE24304), a new aromatase inhibitor, in postmenopausal women. Cancer Res 52:5933-5939, 1992 Submitted July 16, 2007; accepted October 10, 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
4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. 
3 according to the Eastern Cooperative Oncology Group scale, serum alanine aminotransferase or serum aspartate aminotransferase levels more than 3 times the upper normal limit, and a positive history of other types of cancer (except for carcinoma in situ of the cervix or nonmelanoma skin cancer that was radically resected). Patients also were excluded if they had previous treatment with tamoxifen or AIs. 
