Originally published as JCO Early Release 10.1200/JCO.2006.09.4318 on August 20 2007

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Randomized Dose-Ranging Trial of Tamoxifen at Low Doses in Hormone Replacement Therapy Users

Andrea Decensi, Sara Gandini, Davide Serrano, Massimiliano Cazzaniga, Maria Pizzamiglio, Fausto Maffini, Giuseppe Pelosi, Cristina Daldoss, Umberto Omodei, Harriet Johansson, Debora Macis, Matteo Lazzeroni, Mauro Penotti, Laura Sironi, Simona Moroni, Vanda Bianco, Gabriella Rondanina, Jennifer Gjerde, Aliana Guerrieri-Gonzaga, Bernardo Bonanni

From the Divisions of Chemoprevention, Epidemiology and Biostatistics, Radiology, Pathology, Laboratory Medicine, Preventive Gynecology, European Institute of Oncology; Mangiagalli Clinic; Buzzi Hospital, Milan; Division of Gynecology, University of Brescia, Brescia; Division of Medical Oncology, Galliera Hospital, Genoa, Italy; Hormone Laboratory, Haukeland Hospital, University of Bergen; and the Section for Endocrinology, Institute of Medicine, University of Bergen, Bergen, Norway

Address reprint requests to Andrea Decensi, MD, Division of Medical Oncology, Ospedali Galliera, Mura Le capuccine 10, 16128 Genoa, Italy; e-mail: andrea.decensi{at}galliera.it

	ABSTRACT

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Purpose The combination of hormone replacement therapy (HRT) and low-dose tamoxifen may retain the benefits while reducing the risks of either agent. We assessed the optimal biologic dose and schedule of tamoxifen in HRT users using surrogate end point biomarkers and menopausal symptoms.

Subjects and Methods Two hundred ten current or de novo HRT users were randomly assigned to one of the following four arms: tamoxifen 1 mg/day and placebo/week, placebo/day and tamoxifen 10 mg/week, tamoxifen 5 mg/day and placebo/week, or both placebos for 12 months. The primary end point was the change of plasma insulinlike growth factor 1 (IGF-I) through 12 months, and secondary end points were IGF-I/IGF binding protein-3 (IGFBP-3) ratio, fibrinogen, antithrombin III, C reactive protein, C-telopeptide, mammographic percent density, and endometrial thickness. Endometrial proliferation was assessed by Pipelle biopsy in superficial, deep glandular, and stromal compartments after 12 months.

Results Compared with placebo, IGF-I declined in all tamoxifen arms (P = .005), with a greater change on 5 mg/day (P = .019 v 10 mg/week or 1 mg/day). Tamoxifen increased IGFBP-3 and lowered antithrombin-III, C reactive protein, and mammographic density, with greater effects of 5 mg/day. Tamoxifen increased endometrial thickness but not Ki-67 expression, which was lower on 5 mg/day among the three doses. Menopausal symptoms were not significantly worsened by tamoxifen.

Conclusion Doses of tamoxifen 5 mg/day modulate favorably biomarkers of breast carcinogenesis and cardiovascular risk in HRT users with no increase of endometrial proliferation and menopausal symptoms. A dose of 5 mg/day was the most effective and has been selected for a phase III trial in HRT users.

	INTRODUCTION

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Different observations suggest that the combination of hormone replacement therapy (HRT) and tamoxifen may retain the benefits while reducing the risks of either agent. While prolonged use of HRT increases the risk of estrogen receptor–positive breast cancer,¹ patients receiving HRT in the Italian prevention trial had a 60% lower risk of breast cancer in the tamoxifen arm compared with placebo.² In contrast, progestin use has been associated with a favorable effect on the endometrial changes induced by tamoxifen.³ Moreover, premenopausal women in the National Surgical Adjuvant Breast and Bowel Project P-1 prevention trial had no significant increased incidence of endometrial cancer and venous thromboembolic events (VTE).⁴ Finally, in the International Breast Cancer Intervention Study trial, there was evidence of a negative interaction between HRT and tamoxifen on VTE, with no excess of VTE in the tamoxifen arm relative to placebo among HRT users versus an increased risk in non-HRT users.⁵

Our studies indicate that the standard dose of 20 mg/day of tamoxifen may be reduced to 5 mg/day and 1 mg/day without significant loss of its antiproliferative effects on breast cancer.⁶ Because the endometrial effect of tamoxifen is dose dependent,^7,8 a dose reduction could reduce the risk of endometrial cancer while retaining its preventive efficacy. A dose reduction has also been associated with decreased estrogenic effects, including risk factors for VTE such as antithrombin III (AT-III).⁹ Because tamoxifen has a high tissue distribution, the mean breast tissue level attainable with 5 mg/day still exceeds its growth inhibitory concentration in vitro.¹⁰ Moreover, tamoxifen has a half-life of 1 week,¹¹ so a weekly administration is an attractive schedule, particularly in the prevention setting.

The aims of this trial were to assess the optimal biologic dose and schedule of low-dose tamoxifen given for 12 months in HRT users. We used different biomarkers of breast cancer, cardiovascular disease, bone fractures, and endometrial cancer as surrogate end points biomarkers (SEBs),⁶ and investigated the incidence of menopausal symptoms associated with tamoxifen use.

	PATIENTS AND METHODS

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Participants
Study participants were 210 postmenopausal healthy women age younger than 60 years, currently on HRT or about to start it for menopausal symptoms. Participants were enrolled irrespective of HRT route, type, or duration. Exclusion criteria were previous hysterectomy; previous or concurrent malignancy; any type of endometrial or retinal disorders; cataract or glaucoma; history of VTE; active infections; psychiatric disorders or inability to comply to protocol procedures.

The study was conducted at three institutions: the European Institute of Oncology (Milan) and the University Clinics of Gynecology (Brescia and Milan). All sites received institutional review board approval and women signed an informed consent.

Intervention and Study Procedures
A total of 210 women were randomly assigned in a double-blind, double-dummy fashion to one of the following four arms: tamoxifen 1 mg/day and placebo/week, placebo/day and tamoxifen 10 mg/week, tamoxifen 5 mg/day and placebo/week, placebo/day and placebo/week for 12 months. Tamoxifen and placebo tablets were prepared according to good manufacturing practices and blistered in 6-month packages by Monteresearch (Pero, Italy).

Women were assessed at baseline, 6, and 12 months. Blood samples were drawn every 6 months during the combined estrogen/progestin phase. Mammography and transvaginal ultrasound were performed at baseline and after 12 months. An endometrial Pipelle biopsy was performed at 12 months in all consenting participants. In women receiving sequential HRT, baseline and end point transvaginal ultrasound and the Pipelle biopsy were performed between days 6 through 12 of the progestin intake.

Compliance was evaluated by self-reporting calendar, pill count, and blood drug concentration. Adverse events were assessed using the National Cancer Institute Common Toxicity Criteria (version 2). Menopausal symptoms related to tamoxifen use were prespecified and graded as previously reported.¹²

Assay Methods
Fasting blood samples were collected and stored at –80°C until centrally assayed. Plasma insulinlike growth factor 1 (IGF-I) was determined by a chemiluminescent immunometric method (Nichols Institute Diagnostics, San Juan, CA) performed on LIAISON (Diasorin, Saluggia, Italy). Serum insulinlike growth factor I binding protein-3 (IGFBP-3) and high sensitivity C reactive protein were measured by chemiluminescent immunometric kits (DPC, Los Angeles, CA) designed for IMMULITE (Immulite Medical System, Genoa, Italy). IGF-I/IGFBP-3 ratio was calculated after conversion to nmolar concentrations. C-telopeptide was measured by a chemiluminescent immunometric assays designed for Elecsys 1010 (Roche Diagnostics, Basel, Switzerland). Total, high density lipoprotein, low density lipoprotein cholesterol, and triglycerides were measured by enzymatic luminescent methods with COBAS INTEGRA 800 (Roche Diagnostics). Fibrinogen (Clauss method) and AT-III (chromogenic assay) were measured on citrate plasma by ACL 10,000 (Beckman Coulter, Fullerton, CA).

Mammographic percent density was centrally measured on analogic screen films by a single trained radiologist, blinded as to time sequence and treatment arm, at baseline (ie, within 3 months from study entry) and after 12 months, using the computer-assisted method described by Boyd et al.^13,14 Data were not corrected for variations in exposure factors or film processing characteristics, but the same instrument was maintained pre- versus post-treatment.

Endometrial samples were centrally fixed in 4% phosphate-buffered formalin for 12 hours and embedded in paraffin blocks, cut in 4-µm sections, and stained with H&E. Histological diagnosis was categorized into six groups: atrophic/inactive, responsive, simple/complex hyperplasia, polyps, atypical hyperplasia/cancer, and inadequate. Expression of Ki-67 antigen (clone Mib-1; Immunotech, Marseille, France) was detected after dilution 10 µg/mL for 1 hour using the Dako EnVision plus horseradish peroxidase kit (Dako, Milan, Italy) and 3-3'-diaminobenzidine-copper sulfate. Cell percentage showing nuclear immunoreactivity was calculated in superficial, deep glandular, and stromal cells scanning on 10 high power field at 400x. Separation in three tissue compartments follows the different proliferative capacity of these endometrial layers¹⁵ and the preferential effect of tamoxifen on the stromal component.¹⁶

Objectives
The main aim of this study was to test the difference in the percentage change of SEBs of breast cancer, cardiovascular disease, VTE, and osteoporosis between placebo and any tamoxifen dose and, secondly, between 5 mg/day versus 10 mg/week or 1 mg/day, and between 10 mg/week versus 1 mg/day. Safety included testing biomarkers of endometrial cancer and assessing differences on menopausal symptoms between placebo and tamoxifen and among tamoxifen doses.

Outcomes
The main outcome measure was the change in IGF-I from baseline to 12 months. Additional measures were the changes in IGFBP-3, IGF-I/IGFBP-3 ratio, mammographic density, high sensitivity C reactive protein, fibrinogen, AT-III, total cholesterol, triglycerides, C-telopeptide, endometrial thickness, and menopausal symptoms. Endometrial biomarkers assessed only at 12 months included endometrial histology and proliferation.

Sample Size
Using 52 subjects per arm, the study had 80% power to detect a 10% difference between placebo and any tamoxifen dose on the change in IGF-I, ranging from 0% on placebo to 15% on 5 mg/day, with a 20% percent change of the standard deviation.

Random Assignment
Randomization was centrally performed by telephone using permuted blocks of four and participants were stratified according to center and HRT route (oral/transdermal). Study personnel and participants were blinded to treatment assignment for the study duration.

Statistical Methods
Quantitative measurement variables were analyzed through repeated-measure two-way analysis of covariance (ANCOVA) at 6 and 12 months, adjusting for baseline value, center, HRT route, interactions of treatment arms with HRT route, and time. Use of mixed-effect models and the Kenward-Roger technique for determining denominator df were adopted (PROC MIXED; SAS Institute Inc, Cary, NC).¹⁷ For endometrial thickness and mammographic density, where no 6-month data were obtained, a simple ANCOVA model was applied at 12 months, adjusting for baseline, center, and HRT route. For endometrial Ki-67, an ANCOVA model with adjustment for center and HRT route was used. Log or square root transformations were used when necessary to achieve normality. Residual plots assessed the validity of model assumptions. Changes in symptom severity were classified as worsened if the severity score increased after baseline and not worsened if the severity score decreased or was unchanged. Between group differences in symptom score were assessed by a logistic model, with factors for center and HRT route.

Three linear orthogonal contrasts were used to compare the four treatment groups. The first contrast compared the average effect of tamoxifen with placebo. The second and third contrasts were applied to the three tamoxifen arms, one to compare 5 mg/day with 10 mg/week or 1 mg/day and the other to compare 10 mg/week with 1 mg/day. These contrasts were specified a priori and were consistent with the study aims. P values were two sided with 5% significance level. Given the high number of secondary end points, P values except for IGF-I were adjusted for multiple comparisons by Benjamini and Hochberg.¹⁸ All analyses were performed using SAS statistical software version 9.0 (SAS Institute Inc).

	RESULTS

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The participant flow diagram is depicted in Figure 1. Of 611 subjects assessed for eligibility, 282 (46.2%) refused to participate and 119 (19.5%) were not eligible. Of the 210 randomly assigned participants, five were excluded from analysis because baseline IGF-I value was not available. The main subject characteristics are summarized in Table 1. All host and HRT features were evenly distributed among the four treatment arms, including route (transdermal, 54.8%) and duration of HRT (median, 32 months); different types of HRT, such as sequential (80%) or combined regimens (20%); and continuous (94%) or cyclic (6%) schedules. The median and interquartile range of the main circulating biomarkers are summarized in Table 1. There were no significant differences among groups, including lipids and fibrinogen (data not shown).

View larger version (42K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Participant flow diagram.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Effect of tamoxifen on (A) insulinlike growth factor I (IGF-I), (B) antithrombin III, and (C) C-reactive protein.

	DISCUSSION

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While HRT use for prevention of cardiovascular disease in postmenopausal women has been hampered by the results of the Women's Health Initiative trial,¹⁹ a substantial group of younger women will benefit from use of HRT for treatment of climateric syndrome, including BRCA carriers undergoing prophylactic oophorectomy.^20,21 However, the risk of breast cancer associated with HRT is a main barrier for many women, so there is interest for adding agents like tamoxifen that may counteract this risk.² In contrast, the use of tamoxifen is limited by the risk of endometrial cancer and VTE, two events that might be minimized by concomitant use of HRT²² or tamoxifen dose reduction.⁶

Our findings show that tamoxifen given in the range of 1 to 5 mg/day, including 10 mg/week, favorably modulates putative SEBs of breast carcinogenesis, such as IGF-I and mammographic density, and of cardiovascular disease, such as high sensitivity C reactive protein and AT-III, without increasing endometrial proliferation and menopausal symptoms. Admittedly, while there is evidence that the selected biomarkers are associated with increased risk of disease, their role as SEBs of prevention is not yet established. Thus, our findings may simply be reflective of the pharmacologic effectiveness of tamoxifen. Nevertheless, these effects, which are obtained over and above those of HRT, provide strong rationale for assessing in a large trial the efficacy of a combined approach of HRT and low-dose tamoxifen in an attempt to maintain the benefits while reducing the risks of either agent.

Our findings indicate that, relative to placebo, tamoxifen lowered IGF-I and increased its main binding protein IGFBP-3 significantly, so that the ratio between the two components was favorably modulated further. Although high IGF-I²³ and low IGFBP-3²⁴ are important risk biomarkers especially for premenopausal breast cancer, recent data point to their role also in postmenopausal women, particularly during HRT.²⁵ This may be due to the sensitizing effect of endogenous or exogenous sex steroids on the IGF-regulated effect on the breast gland,^26,27 which may be inhibited by tamoxifen through its direct inhibition on IGF-I production.^28,29 Likewise, any tamoxifen dose and particularly 5 mg/day induced a borderline significant reduction of mammographic density, a well-established risk biomarker of breast cancer¹³ and a promising SEB, since its reduction under tamoxifen is associated with a lowered risk of breast cancer.³⁰ Importantly, HRT has been shown to increase mammographic density and this effect may diminish mammography sensitivity and increase breast cancer risk associated with combined HRT use.¹ It is calculated that an increase in density of 1% translates into a 2% higher risk of developing breast cancer.¹³ Thus, the decrease by 4% to 5% of mammographic density by tamoxifen 5 mg/day for 1 year may lower breast cancer risk by 8% to 10% and increase mammography sensitivity appreciably.

Among cardiovascular disease SEBs, tamoxifen modulated favorably high sensitivity C reactive protein and AT-III, but not lipids and fibrinogen, and 5 mg/day was superior to the lower doses in modulating both biomarkers. The prominent role of high high sensitivity C reactive protein as a cardiovascular risk biomarker in women has been established in prospective studies,^31,32 including an explanation for the potential harm associated with oral HRT use versus the null effect of transdermal estradiol.³³ Moreover, high sensitivity C reactive protein is increasingly recognized as a risk factor in human carcinogenesis, and high sensitivity C reactive protein–reducing compounds like statins are being tested as preventive agents.³⁴ Conversely, the role of low AT-III levels as a risk factor for VTE is unclear, although studies suggest a possible correlation.⁹ Interestingly, the reduction of AT-III on low-dose tamoxifen was marginal relative to 20 mg/day, thus suggesting a better safety profile. Clearly, the association between tamoxifen dose and risk of VTE in HRT women is important in assessing the cost:benefit ratio of the combined approach, and further studies are necessary to address this issue. We found no modulation on lipids and fibrinogen by low-dose tamoxifen, which may be explained by the loss of estrogenicity associated with dose reduction.⁶ A similar mechanism may explain the lack of modulation of C-telopeptide, a biomarker of bone fracture.³⁵ Indeed, tamoxifen 20 mg/day was as effective as raloxifene, a drug registered for osteoporosis, in reducing bone fracture risk in the Study of Tamoxifen and Raloxifene trial.³⁶ Thus, a dose reduction may be associated with a partial loss of adverse and favorable effects of tamoxifen on VTE and bone fractures, respectively.

Importantly, we found no effect of tamoxifen at low doses on endometrial tissue biomarkers. While endometrial thickness was significantly augmented, this was not associated with histological alterations, nor was there an increase in cell proliferation. While our results underline the difference between ultrasound and histological/immunohistochemical effects of tamoxifen, which may be explained by the stromal hypertrophy,¹⁶ it is noteworthy that treatment with tamoxifen 20 mg/day has been associated with increased proliferation and histological abnormalities in several studies.^37,38 Because Ki-67 is a risk biomarker for endometrial carcinogenesis,³⁹ which is augmented by tamoxifen 20 mg/day in hyperplastic or premalignant tissue,^40,41 our results suggest that a dose reduction leads to a lower risk of endometrial cancer. Further studies are necessary to confirm this important finding.

Menopausal symptoms frequently associated with the standard dose of tamoxifen, particularly hot flashes, vaginal discharge, and sweating, were not significantly increased on low-dose tamoxifen compared with placebo. Our data support the notion that a dose reduction and the concomitant use of HRT does limit the occurrence of bothersome vasomotor and gynecological symptoms, which reach 40% to 50% in primary prevention trials of tamoxifen or raloxifene.^12,42 In a retrospective analysis of the International Breast Cancer Intervention Study trial, HRT use at entry and during the trial was not effective in alleviating hot flashes associated with tamoxifen 20 mg/day.⁴³ Because tamoxifen is extremely lipophylic and easily passes the brain barrier,⁴⁴ a lower saturation of the ER in the CNS with tamoxifen at a lower dose might explain the lower rate of hot flashes worsening noted in our study.

A general theme of our study was the greater biomarker modulation by 5 mg/day versus the two lower doses, which was noted on IGF-I, IGFBP-3, mammographic density, AT-III, and high sensitivity C reactive protein. Intriguingly, 5 mg/day exhibited a lower endometrial proliferation than the two lower doses, suggesting a complex pharmacodynamic effect. Altogether, these results indicate that 5 mg/day was the most effective and the safest dose to be assessed in a phase III trial.²² However, the finding that a weekly administration of 10 mg still exerts a significant modulation of several biomarkers over and above the effects of HRT deserves further investigation in a prevention setting.

In conclusion, tamoxifen at low doses favorably modulates biomarkers of breast carcinogenesis and cardiovascular risk in HRT users without increasing endometrial proliferation and with limited symptom worsening. A large phase III trial of tamoxifen 5 mg/day versus placebo is underway in women on HRT to assess the efficacy of this combined approach.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Andrea Decensi, Umberto Omodei, Bernardo Bonanni

Financial support: Andrea Decensi

Administrative support: Aliana Guerrieri-Gonzaga

Provision of study materials or patients: Cristina Daldoss, Umberto Omodei, Mauro Penotti, Laura Sironi, Vanda Bianco, Bernardo Bonanni

Collection and assembly of data: Davide Serrano, Massimiliano Cazzaniga, Maria Pizzamiglio, Fausto Maffini, Giuseppe Pelosi, Cristina Daldoss, Harriet Johansson, Debora Macis, Matteo Lazzeroni, Mauro Penotti, Simona Moroni, Gabriella Rondanina, Jennifer Gjerde, Aliana Guerrieri-Gonzaga

Data analysis and interpretation: Andrea Decensi, Sara Gandini

Manuscript writing: Andrea Decensi, Sara Gandini, Aliana Guerrieri-Gonzaga

Final approval of manuscript: Andrea Decensi, Sara Gandini, Davide Serrano, Massimiliano Cazzaniga, Maria Pizzamiglio, Fausto Maffini, Giuseppe Pelosi, Cristina Daldoss, Umberto Omodei, Harriet Johansson, Debora Macis, Matteo Lazzeroni, Mauro Penotti, Laura Sironi, Simona Moroni, Vanda Bianco, Gabriella Rondanina, Jennifer Gjerde, Aliana Guerrieri-Gonzaga, Bernardo Bonanni

	Appendix

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The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®).

	ACKNOWLEDGMENTS

 
We thank Massimo Surace for his thorough clinical assistance and Giorgia Bollani for her excellent data management support.

	NOTES

 
published online ahead of print at www.jco.org on August 20, 2007.

Supported by grant No. BCTR01-00537 from the S. Komen Breast Cancer Foundation and the Italian Health Ministry (Ricerca Finalizzata); a fellowship from Gruppo Bancario Credito Valtellinese and the European School of Oncology; and a contract from the Italian Foundation for Cancer Research.

Presented in part at the American Association for Cancer Research Frontiers in Cancer Prevention Research conference, Baltimore, MD, October 29 to November 3, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted October 16, 2006; accepted March 28, 2007.

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