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Feb 12, 2014 - CLINICAL TRIAL. Effect of adjuvant endocrine therapy on hormonal levels in premenopausal women with breast cancer: the ProBONE II study.
Breast Cancer Res Treat (2014) 144:343–351 DOI 10.1007/s10549-014-2860-7

CLINICAL TRIAL

Effect of adjuvant endocrine therapy on hormonal levels in premenopausal women with breast cancer: the ProBONE II study Peyman Hadji • Annette Kauka • May Ziller • Katrin Birkholz • Monika Baier • Mathias Muth Peter Kann



Received: 13 December 2013 / Accepted: 23 January 2014 / Published online: 12 February 2014 Ó Springer Science+Business Media New York 2014

Abstract Endocrine therapy (ET) is a key treatment modality in hormone receptor positive (HR?) early breast cancer (BC) patients. Although the anticancer activity of adjuvant ET ? zoledronic acid (ZOL) has been investigated, the potential effects of ET ± ZOL on endocrine hormones in premenopausal women with HR? early BC are not well understood. ProBONE II was prospective, double-blind, randomized controlled trial. Premenopausal patients with histologically confirmed invasive BC with no evidence of metastases and a T score [-2.5 received

Katrin Birkholz was an employee of Novartis Pharma GmbH at the time of study conduct and during manuscript development until November 28, 2013.

Electronic supplementary material The online version of this article (doi:10.1007/s10549-014-2860-7) contains supplementary material, which is available to authorized users. P. Hadji (&)  A. Kauka  M. Ziller Department of Endocrinology, Reproductive Medicine and Osteoporosis, Philipps - University of Marburg, Baldingerstrasse, 35033 Marburg, Germany e-mail: [email protected] K. Birkholz  M. Muth BU Oncology, Novartis Pharma GmbH, Roonstraße 25, 90429 Nuernberg, Germany M. Baier Clinical & Regulatory Affairs/Biometrics Department, Novartis Pharma GmbH, Roonstraße 25, 90429 Nuernberg, Germany P. Kann Department of Endocrinology and Diabetes, Philipps University of Marburg, 35033 Marburg, Germany

ET ± ZOL 4 mg every 3 months for 2 years. Serum levels of estradiol (E2), follicle-stimulating hormone, anti-muellerian hormone (AMH), inhibins A and B, sex hormonebinding globulin, parathyroid hormone, total testosterone, and vitamin D were evaluated at baseline and at every scheduled visit. Of 71 women enrolled, 70 were evaluable (n = 34, ZOL; n = 36, placebo). No statistically significant differences were observed in hormone levels, except E2 and AMH, which showed minor differences. These included decreases in serum E2 levels, which reached a nadir after 3 and 9 months in placebo and ZOL groups, respectively, and decrease in serum AMH levels throughout the study with ZOL, but remained constant with placebo after 6 months. Adverse events in ZOL-treated group were influenza-like illness (32.4 %), bone pain (32.4 %), chills (20.6 %), and nausea (23.5 %). ET ± ZOL was well tolerated. This study showed no influence of ZOL on hormonal level changes that accompany ET, supporting inclusion of ZOL in adjuvant therapy for premenopausal women with HR ? BC. Keywords Adjuvant  Endocrine therapy  Hormone receptor-positive breast cancer  Premenopausal  Serum hormones  Zoledronic acid Abbreviations AE Adverse event AI Aromatase inhibitor AMH Anti-muellerian hormone ANCOVA Analysis of covariance BMD Bone mineral density CI Confidence interval DFS Disease-free survival DXA Dual energy X-ray absorptiometry E2 Estradiol

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ER ET FSH GnRH HR ? BC ITT IV ONJ OS PTH SAE SD SHBG

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Estrogen receptor Endocrine therapy Follicle-stimulating hormone Gonadotropin-releasing hormone Hormone receptor-positive breast cancer Intent-to-treat Intravenous Osteonecrosis of the jaw Overall survival Parathyroid hormone Serious adverse event Standard deviation Sex hormone-binding globulin

Introduction Endocrine therapy (ET) forms a key modality of adjuvant treatment and has a positive impact on overall survival (OS) in patients with estrogen receptor (ER)-positive breast cancer (BC) [1]. ET aims to modulate and disrupt estradiol (E2) function through the disruption of ER-mediated signaling with anti-estrogens and/or reduction in circulating E2 levels through ovarian suppression or aromatase inhibitor (AI) therapy. In addition, chemotherapy regimens for the treatment of BC in premenopausal women may lead to amenorrhea and early menopause [2–4]. The incidence of amenorrhea, a surrogate for disruption of normal hormonal signaling, dramatically increases in premenopausal patients undergoing chemotherapy, and is dependent on age and the specific treatment regimens used [5]. Hence, both endocrine and chemotherapeutic agents can disrupt normal hormonal signaling and increase bone loss in patients with early stage BC [4, 6]. The bone sub-study of the large ABCSG-12 trial of premenopausal women receiving ET (goserelin and anastrozole) showed that the mean percentage decrease in bone mineral density (BMD) at the lumbar spine was 7.4 % in the first year and 11.3 % over 3 years [7]; however, neither hormone levels nor bone markers were assessed in ABCSG-12. Antiresorptive agents like the nitrogen-containing bisphosphonate zoledronic acid (ZOL) or a mAb like denosumab [8] are used as adjuvant treatment for BC to preserve or improve BMD during treatment. Treatment with ZOL has been shown to improve disease-free survival (DFS), OS, and disease outcomes for subsets of patients in three large clinical trials [9–11]. However, the effects of ET ± ZOL on hormonal changes that occur during cancer treatment are largely unknown. The complex regulation of normal bone turnover involves both systemic and local factors. Major systemic

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regulators of bone include parathyroid hormone (PTH), vitamin D, sex hormones, and gonadotropins such as follicle-stimulating hormone (FSH). The critical role of E2 in bone remodeling involves both the prevention of osteoclast formation and the stimulation of osteoblast proliferation [12]. E2 exerts its pleiotropic effect on bone through transcription of enzymes and bone matrix proteins, interaction with hormone receptors and transcription factors, and via upregulation of local growth factors such as inhibins A and B. Inhibins themselves exert direct effects on osteoblastogenesis and osteoclastogenesis, and decreases in their levels are associated with increased bone turnover and bone mass regardless of changes in E2 or FSH [13]. Withdrawal of E2 at menopause leads to indirect stimulation of osteoclasts through production of inflammatory cytokines, such as interleukin (IL)-1 and tumor necrosis factor alpha (TNF-a) leading to concomitant increase in bone resorption [14]. Endocrine therapy abates this effect. In premenopausal patients with BC, 2 studies have investigated a second-generation AI and gonadotropinreleasing hormone (GnRH) analog, which were found to strongly suppress E2 secretion [15, 16]. A phase I trial further investigated the effects of ET (goserelin ? anastrozole) in premenopausal women with advanced BC. ET with goserelin ? tamoxifen resulted in tumor progression in these patients, while substituting tamoxifen with anastrozole led to a 76 % further reduction in E2 serum levels [17]. However, there is a paucity of published evidence regarding the potential influence of ET ± ZOL on hormone levels besides E2 in premenopausal women receiving adjuvant therapy for early BC. Many studies have investigated the effect of the ERa/b ratio and ERb as predictors of ET responsiveness in premenopausal women with BC [18]. However, the change in hormonal levels on ET is unclear. The ProBONE II study (NCT00375505) is the first to evaluate the endocrine effects of adjuvant therapies ± ZOL on hormone levels in premenopausal women with HR ? early BC. The objectives of the current analysis were to assess the effects of adjuvant ET ± ZOL on endocrine hormone levels including E2, PTH, FSH, anti-muellerian hormone (AMH), inhibins A and B, sex hormone-binding globulin (SHBG), total testosterone, and vitamin D in premenopausal women at various time points during 2 years of ET.

Materials and methods Patient population Premenopausal women, as determined by spontaneous and regular menses or E2 levels [20 ng/L at diagnosis of BC,

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and C18 years of age with HR ? early BC (defined as C10 % receptor-positive cells or C10 fmol receptor protein/mg cytosolic protein) were eligible for this study if they had histologically confirmed invasive BC (T1-4), no evidence of metastases (M0), were receiving neoadjuvant or adjuvant chemotherapy and/or ET with approved standard regimen(s), and had a T-score at study entry [-2.5. Patients receiving neoadjuvant treatment were required to have no nodal involvement; patients receiving adjuvant treatment were required to have no more than four positive lymph nodes. On-study ZOL and placebo therapy commenced within the first two cycles of adjuvant anticancer therapy. Additional neoadjuvant agents were permitted. Exclusion criteria included a history of treatment or disease-affecting bone metabolism, or known visceral or bone metastases. Patients with previous treatment with or hypersensitivity to bisphosphonates, dental issues including osteonecrosis of the jaw (ONJ), planned or recent dental or jaw surgery, and renal impairment (i.e., creatinine clearance \30 mL/min using the Cockcroft-Gault formula) were ineligible. The study was approved by the institutional ethics committee, and all patients provided written informed consent before starting study procedures. Premenopausal patients enrolled up to June 2009 were included in this analysis. Study design This study was a prospective, single-center, randomized, double-blind, placebo-controlled trial. Patients received adjuvant ET that included either GnRH analogs (goserelin 3.6 mg or goserelin acetate 3.8 mg) or anti-estrogens (tamoxifen 20 mg daily) for 24 months. Some patients also received chemotherapy with standard cytotoxic drugs (anthracycline-cyclophosphamide, followed by a taxane and fluorouracil). After a baseline period of 4 weeks for eligibility assessment, patients were randomized to receive either ZOL 4 mg intravenous (IV) over 15 min or placebo, starting within the first two cycles of adjuvant treatment and administered every 3 months for 2 years, for a total of 8 study-drug infusions (Fig. 1). Study visits were scheduled at approximately 3, 6, 9, 12, and 24 months after random assignment. Safety was assessed by determining the frequency of adverse events (AEs) and changes in laboratory values at each visit during the study period. Serum biomarkers All serum samples were collected early in the morning, following an overnight fast. Samples were immediately stored at -90 °C and used for assessment of serum

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Premenopausal women with HR+ early breast cancer N = 70

(Neo)Adjuvant Endocrine therapy (± chemotherapy) + Placebo IV q 3 months n = 36 24 months

(Neo)Adjuvant Endocrine therapy (± chemotherapy) + ZOL 4 mg IV q 3 months n = 34 24 months

3-year Follow-up

Change in BMD Change in hormones Change in bone turnover markers Safety, fractures

Fig. 1 Study schema for ProBONE II. Abbreviations: BMD bone mineral density, HR? hormone receptor-positive, IV intravenous, q every, ZOL zoledronic acid

hormones, including E2, PTH, FSH, SHBG, total testosterone, and vitamin D levels, at baseline (before treatment start, regardless of menstrual cycle) and at each scheduled visit. Serum inhibin A, inhibin B, and AMH levels were assessed at baseline and at 6, 12, and 24 months only using an enzyme-linked immunosorbent assay (Beckman Coulter GmbH, Krefeld, Germany). E2 levels were measured by the Estradiol RIA Test (Radim Deutschland GmbH, Freiburg, Germany) and confirmed by a more sensitive Electrochemiluminescence Immunoassay (ECLIA; Roche Diagnostics GmbH, Mannheim, Germany). Measurements of PTH, FSH, SHBG, total testosterone, and vitamin D were also performed using ECLIA (Roche Diagnostics GmbH). Statistical analysis Sample size calculation was based on treatment effect on BMD (primary endpoint, published elsewhere) of the lumbar spine measured by dual energy X-ray absorptiometry (DXA) of 0.16 g/cm2 and a common standard deviation (SD) of 0.18, observed in a previous study on bone loss during adjuvant chemo-endocrine therapy in a similar patient population [19]. To achieve 90 % power with a two-sided 5 % significance level, 28 patients in each group were required. To account for dropout, a total of 70 patients were randomized. Comparison of study arms with respect to the primary endpoint was performed using an analysis of covariance (ANCOVA) model, including type of ET, ZOL versus placebo treatment, and baseline BMD as covariates. Differences in hormonal levels were assessed

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(a)

Table 1 Patient characteristics at baseline

Mean age, years (range) Caucasian

Patients, n (%) Placebo (n = 36)

ZOL (n = 34)

42.8 (26–51)

43.2 (23–51)

35 (97.2)

34 (100)

ER/PgR status ER-, PgRER?, PgR? ER?, PgR– ER-, PgR? TNM classification T1 T2–T3 N0 N1–N2 M0 R0 classification

0 (0) 32 (88.9)

Placebo ZOL

70

0 (0) 31 (91.2)

3 (8.3)

1 (2.9)

1 (2.8)

2 (5.9)

Estradiol-RIA, pg/mL

ITT population

80

60 50 40 30 20 10

29 (80.6)

23 (67.6)

7 (19.4)

11 (32.4)

29 (80.6)

29 (85.3)

7 (19.4)

5 (14.7)

36 (100)

34 (100)

35 (97.2)

34 (100)

Base

Month 3

Month 6

Month 9

Month 12

Month 24

Visit report number

(b) 30

Placebo ZOL

G1

8 (22.2)

9 (26.5)

G2

21 (58.3)

22 (64.7)

G3

7 (19.4)

3 (8.8)

Planned adjuvant treatment Endocrine treatment Tamoxifen

34 (94.4)

32 (94.1)

0 (0) 5 (13.9)

1 (2.9) 3 (8.8)

32 (88.9)

27 (79.4)

17 (47.2)

17 (50.0)

Taxanes

13 (36.1)

12 (35.3)

Cyclophosphamide

17 (47.2)

17 (50.0)

8 (22.2)

7 (20.6)

33 (91.7)

30 (88.2)

Raloxifene Aromatase inhibitors GnRH analogs Chemotherapy Anthracyclines

Fluorouracil Radiotherapy

ER estrogen receptor, ITT intent-to-treat, PgR progesterone receptor, GnRH gonadotropin-releasing hormone, ZOL zoledronic acid

using adjusted least-square means with two-sided 95 % confidence intervals (CI) and two-sided P values in the intent-to-treat (ITT) populations.

FSH, mIU/mL

Tumor grade 20

10

0 Base

Month 3

Month 6

Month 9

Month 12

Month 24

Visit report number

Fig. 2 Changes in mean a serum estradiol levels, and b FSH levels over time in placebo- versus ZOL-treated premenopausal patients with HR ? BC. Abbreviations: FSH follicle-stimulating hormone, HR ? BC hormone receptor-positive breast cancer, mIU million international units, RIA radioimmunoassay, ZOL zoledronic acid

predominant diagnosis of T1 N0-1 M0 BC and a mean age of 43 years (range, 23–51 years). Adjuvant ET involved a GnRH analog (84.3 %) or tamoxifen (94.3 %) for the majority of patients; four patients (11.1 %) in the placebo group and seven patients (20.6 %) in the ZOL group did not receive GnRH analogs (Table 1).

Results

Changes in serum hormone levels

Patient characteristics

Of 70 patients treated with ET ± ZOL, there were no statistically significant differences observed in serum hormone levels, regardless of treatment with ZOL or placebo, at any time point during the study. A sub analysis of patients in ZOL and placebo groups treated with endocrine therapy (GnRH analogs and tamoxifen) alone showed no statistically significant differences in serum hormone levels between both the treatment groups (supplementary

From October 2005 to June 2009, a total of 71 premenopausal women with HR ? BC received ET and were randomized to treatment with either ZOL (n = 34) or placebo (n = 36) (Fig. 1). One patient was excluded from the ITT population due to withdrawal of consent, and was not included in the efficacy or safety analyses. Patients had a

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(a) 1.2 Placebo ZOL

AMH, ng/mL

1 0.8 0.6 0.4 0.2 0

Base

Month 3

Month 6

Month 9

Month 12

Month 24

Visit report number

(b)

30 Placebo ZOL

Inhibin A, pg/mL

25 20 15 10 5 0

Base

Month 3

Month 6

Month 9

Month 12

Month 24

Visit report number

(c)

50 Placebo ZOL 40

Inhibin B, pg/mL

Table 1). In supplementary Table 2, the median ± interquartile ranges for serum hormone levels analyzed (from baseline to end of study) in all patients are presented. The overall serum E2 levels (Estradiol-RIA, pg/mL) decreased in all patients over the 2-year course of this study (mean ± SD, 56.01 ± 118.76 [baseline] to 22.27 ± 69.74 [at month 24]) as seen in Fig. 2a in both treatment groups. Though not statistically significant, minor differences in E2 levels were observed between ZOL and placebo groups up to month 6, showing a slight delay in patients who received ZOL until 12-months of study-treatment (33.20 ± 29.12 [mean ± SD, at baseline] and 11.98 ± 9.72 [mean ± SD, at month 12] in ZOL group vs. 77.55 ± 161.32 [mean ± SD, at baseline] and 12.98 ± 11.65 [mean ± SD, at month 12] in placebo group). In addition, some patients in the ZOL group had extremely high E2 levels. E2 levels increased again at month 24 in patients treated with ZOL (33.20 ± 29.12 [mean ± SD, at baseline] to 32.89 ± 98.54 [mean ± SD, at month 24]), suggesting that fewer patients in the ZOL group received GnRH analogs compared with patients in the placebo group. A trend for decelerated E2 reduction was observed in patients 40 years of age or younger (data not shown). However, this subpopulation was too small (8 ZOL-treated and 11 placebotreated patients) to make any firm conclusions. FSH levels (mIU/mL) (11.16 ± 13.63 [mean ± SD, at baseline, all patients]) increased after 3 months of therapy (27.34 ± 36.75 [mean ± SD, at month 3, all patients]), but returned to near baseline levels by the end of the treatment period (11.42 ± 28.64 [mean ± SD, at month 24, all patients]) (Fig. 2b), with no statistically significant differences observed between treatment groups. AMH levels (ng/mL) (0.96 ± 1.99 [mean ± SD, at baseline, placebo group]; 1.09 ± 2.02 [mean ± SD, at baseline, ZOL group]) decreased by 57 % in placebotreated and by 70 % in ZOL-treated patients after 6 months of treatment (0.41 ± 1.24 [mean ± SD, at month 6, placebo group]; 0.33 ± 0.62 [mean ± SD, at month 6, ZOL group]). AMH levels further decreased until month 12 in ZOL-treated patients (0.22 ± 0.30 [mean ± SD, at month 12]), whereas in the placebo group (0.38 ± 1.31 [mean ± SD, at month 12]), they remained constant after 6 months (Fig. 3a). Inhibin A (pg/mL) (21.97 ± 24.78 [mean ± SD, at baseline, all patients]) and inhibin B (pg/mL) (37.14 ± 41.42 [mean ± SD, at baseline, all patients]) decreased by month 6 (7.01 ± 7.03 [mean ± SD, inhibin A, all patients]; 6.63 ± 11.98 [mean ± SD, inhibin B, all patients]), and levels remained low for the remainder of the 24-month study period (7.54 ± 11.48 [mean ± SD, inhibin A, all patients]; 3.94 ± 5.79 [mean ± SD, inhibin B, all patients]) (Fig. 3b, c), with no significant differences

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30

20

10

0

Base

Month 3

Month 6

Month 9

Month 12

Month 24

Visit report number

Fig. 3 Mean changes in a AMH, b inhibin A, and c inhibin B levels over time in placebo- versus ZOL-treated premenopausal patients with HR ? BC. Abbreviations: AMH anti-muellerian hormone, HR ? BC hormone receptor-positive breast cancer, ZOL zoledronic acid

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(a) 120

(b) 0.35

Placebo ZOL

Testosterone, ng/mL

SHBG, nmol/L

110

100

90

80

Base

Placebo ZOL

0.3

0.25

0.2

Month 3

Month 6

Month 9

Month 12

Month 24

Base

Month 3

Visit report number

Month 9

Month 12

Month 24

Visit report number

(d)

Placebo ZOL

36 34

Vitamin D, ng/mL

PTH, pg/mL

(c) 45

Month 6

40

35

Placebo ZOL

32 30 28 26 24 22

30

Base

20

Month 3

Month 6

Month 9

Month 12

Month 24

Base

Visit report number

Month 3

Month 6

Month 9

Month 12

Month 24

Visit report number

Fig. 4 Changes in a SHBG, b total testosterone, c PTH, and d vitamin D over time in placebo- versus ZOL-treated premenopausal patients with HR ? BC. Abbreviations: HR ? BC hormone receptor-

positive breast cancer, PTH parathyroid hormone, SHBG sex hormone-binding globulin, ZOL zoledronic acid

between ZOL- and placebo-treated patients. A careful sub analysis of patients treated with endocrine therapy alone versus patients treated with endocrine therapy plus chemotherapy showed a similar decline in inhibin A and B levels, from baseline to end of study. The levels of total testosterone, SHBG, and PTH increased slightly during the 2-year treatment period (testosterone [ng/mL]: from 0.28 ± 0.12 at baseline to 0.31 ± 0.13 at month 24 [mean ± SD, all patients]; SHBG [nmol/ L]: from 91.50 ± 47.31 at baseline to 101.24 ± 40.50 at month 24 [mean ± SD, all patients]; PTH [pg/mL]: from 31.58 ± 11.28 at baseline to 37.33 ± 13.37 at month 24 [mean ± SD, all patients]) (Fig. 4a–c). A trend toward slightly higher total PTH levels (pg/mL) was observed in placebo versus ZOL-treated patients (30.81 ± 10.33 at baseline to 37.55 ± 15.85 at month 24 [mean ± SD, placebo group] versus 32.38 ± 12.28 at baseline to 37.11 ± 10.46 at month 24 [mean ± SD, ZOL group]). However, by 24 months, there were no statistically significant differences observed in patients irrespective of ZOL or placebo treatment.

Levels of vitamin D (ng/mL) were similar (23.40 ± 10.92 [mean ± SD, at baseline, all patients]) and continued to increase throughout the study in both treatment groups (33.77 ± 11.71 [mean ± SD, at month 24, all patients]) (Fig. 4d), presumably due to consequences of calcium and vitamin D supplementation per the trial protocol.

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Safety All patients included in the safety analysis (N = 70) reported an AE. Two patients receiving ZOL and 1 patient receiving placebo discontinued treatment due to an AE. The most frequently reported treatment-emergent AEs (Table 2) included influenza-like illness (consistent with an acute-phase reaction following ZOL administration), arthralgia, hot flushes, lymphedema, menopausal symptoms, and bone pain. Serious AEs (SAEs) were reported in six patients (17.6 %) in the ZOL group and three patients (8.3 %) in the placebo group. Only 1 study drug-related SAE (ONJ) was reported; however, this patient had undergone a dental

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Table 2 Treatment-emergent adverse events reported in [10 % of patients Adverse event

Patients, n (%) Placebo (n = 36)

ZOL (n = 34)

Arthralgia

22 (61.1)

16 (47.1)

Hot flush

20 (55.6)

16 (47.1)

Lymphedema Menopausal symptoms

19 (52.8) 14 (38.9)

11 (32.4) 16 (47.1)

Bone pain

12 (33.3)

11 (32.4)

Sleep disorders

7 (19.4)

2 (5.9)

Paresthesia

6 (16.7)

4 (11.8)

Nausea

5 (13.9)

8 (23.5)

Influenza-like illness

4 (11.1)

11 (32.4)

Back pain

4 (11.1)

4 (11.8)

Headache

3 (8.3)

6 (17.6)

Chills

1 (2.8)

7 (20.6)

ZOL zoledronic acid

extraction during therapy. An additional suspected case of mild ONJ in a ZOL-treated patient was later confirmed to be periodontitis. No deaths were reported during the study.

Discussion The rationale for the ProBONE II study was to assess the effect of adjuvant ET ± ZOL on endocrine hormone levels in premenopausal women with HR ? early BC. Our data showed no statistically significant differences in serum hormone levels regardless of treatment with ZOL or placebo at any time point during the study. E2 levels were suppressed over the 2-year treatment period (± ZOL), although it cannot be completely excluded that there was a few months’ delay in the decline of E2 levels with ZOL. This delay in suppression of E2 levels might have possibly been caused by the smaller proportion of patients in the ZOL group-receiving GnRH analogs during the 3rd and 6th month of treatment. In addition, some patients in the ZOL group had relatively high E2 levels compared with the placebo group. These results are similar to short-term findings in both premenopausal and postmenopausal women, in whom ZOL did not impact hormone levels when assigned to letrozole for up to 1 year [20, 21]. In the prospective Hormonal Adjuvant Treatment Bone Effects (HOBOE) study, 6 months of treatment with letrozole ± ZOL (4 mg, every 6 months), was compared with tamoxifen in 81 premenopausal patients with early BC. Letrozole ± ZOL-caused significantly greater suppression of E2 and less suppression of FSH compared with tamoxifen; the addition of ZOL to letrozole did not affect hormone levels [20].

Two studies, ABCSG-12 and AZURE, were similar to ProBONE II as they were performed in patients with HR ? BC and used ET ± ZOL. However, the anticancer benefit of ZOL and whether its effect was mediated through hormonal levels was investigated in these studies. In the preplanned subgroup analyses of the large ABCSG-12 [22] and AZURE trials [10], adding ZOL (4 mg, every 3 or 6 months) to adjuvant ET showed greatest benefit in patients expected to have very low levels of E2 and related hormones (i.e., women undergoing ovarian ablation or women who were more than 5 years postmenopausal). In the ABCSG-12 study, analyses of age-defined subgroups showed no significant DFS (hazard ratio = 0.91; log-rank P = 0.707) or OS (hazard ratio = 1.01; log-rank P = 0.982) benefits with ZOL in women B40 years of age (n = 413), whereas adding ZOL to adjuvant ET significantly reduced the risk of DFS events by 34 % (hazard ratio = 0.66; log-rank P = 0.013) and of death by 49 % (hazard ratio = 0.51; log-rank P = 0.018) in women[40 years of age (n = 1390) [10, 22]. These data are consistent with the AZURE subgroup analyses, wherein significant DFS and OS benefits were observed in the established ([5 years) postmenopausal patient subset [10]. However, neither the AZURE nor ABCSG-12 trials directly measured E2 levels. Taken together, the data from the AZURE and ABCSG-12 trials suggest that the anticancer effects of ZOL observed in low estrogen environments generated by ET or menopause are not mediated through effects of ZOL on hormone levels; ZOL could provide additional support in mediating direct anticancer effects to explain its DFS benefit. During the course of our study, mean serum vitamin D levels increased similarly in both patient groups, likely because of the calcium and vitamin D supplementation per the trial protocol. A trend toward higher levels of total testosterone and PTH was observed in patients with ZOL, albeit without statistical differences between groups with or without ZOL. Studies investigating the influence of ZOL have used different dosing regimens making it difficult to compare between studies, such as the KCSG-BR06-01 study, in which ZOL was initiated concurrently with chemotherapy and administered every 6 months [23]. Using less frequent ZOL administration and a more heterogeneous patient population makes it difficult to compare hormonal changes between the KCSG-BR06-01 and ProBONE II study. In addition, as there is no established ZOL dosing schedule in the adjuvant BC setting, studies have used different timings for treatment with ZOL (typically every 3 or 6 months). In our study, more frequent dosing of ZOL (every 3 months) was used. If ZOL were to influence hormonal levels, our dosing schedule would have most likely showed an effect. Changes in the levels of E2, inhibins A and B, AMH, and FSH from our study suggest a rapid and sustained

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decline in ovarian function during adjuvant ET. This rapid and significant suppression of E2 might ultimately translate into a higher incidence of long-term side effects including osteoporosis, fractures, changes in lipid metabolism, and subsequent cardiovascular disease. Given the improved survival of premenopausal patients with early BC, the clinical importance of managing the long-term health risks that accompany E2 suppression has become increasingly relevant. In the ProBONE II study, the majority of patients received standard endocrine regimens (± chemotherapy), including a GnRH analog and tamoxifen. The hormonal effects of 2 years of treatment with these regimens are consistent with what was reported earlier [24]. We do acknowledge the fact that patients in this study treated with chemotherapy may have experienced chemotherapyinduced transient suppression of ovarian function, which may not have had a major influence under the study conditions. Further, treatment with AIs like anastrozole or letrozole was shown to promote the recovery of ovarian function in premenopausal patients with chemotherapyinduced amenorrhea [25]. Common weaknesses of this study are the inclusion of a very small cohort of patients with heterogeneous treatments ± ZOL, narrow ethnic representation of patient population, single center study, hormonal values at baseline were obtained after inclusion of patients into the study regardless of menstrual cycle, and the timing of the hormonal level assessments that could have missed some rapid changes in hormonal levels during treatment with ZOL, although the clinical significance of any rapid hormonal changes versus longer-term trends observed over our 2-year study is unclear. In conclusion, our study demonstrated that ET ± ZOL in premenopausal patients with HR ? BC is well tolerated and does not affect hormone levels. As a growing body of evidence supports adding ZOL to adjuvant ET to preserve bone health, these data add further support that the addition of ZOL to ET does not affect the efficacy of ET by reducing serum E2 and related hormone levels. Thus, the use of GnRH analogs and tamoxifen together with ZOL offers a valuable therapeutic option in premenopausal women with HR ? BC. Additional studies are needed to evaluate the endocrine effects of using hormonal therapy in a larger patient cohort with HR ? BC and with longer follow-up. Acknowledgments This study was sponsored by Novartis Pharma GmbH. We thank Lakshmikanth Tadepally, Novartis Health Care Pvt. Ltd., for providing medical editorial assistance with this manuscript. The authors thank all study participants. Ethical standards The study was performed in compliance with the current laws of Germany in which the trial was performed.

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Breast Cancer Res Treat (2014) 144:343–351 Conflict of interest P. Hadji has received honoraria and unrestricted educational grants from Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and Roche. A. Kauka and P. Kann have no conflicts to declare. M. Ziller has received honoraria and unrestricted educational grants from Eli Lilly, Gedeon Richter Pharma GmbH, Jenapharm GmbH & Co., KG, DR. KADE Pharma GmbH, Rottapharm/Madaus GmbH, Novartis, and Pfizer. M. Baier, M. Muth, and K. Birkholz (until November 28, 2013) are employed by Novartis Pharma GmbH.

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