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Journal of Clinical Oncology, Vol 24, No 1 (January 1), 2006: pp. 129-135
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.02.9934
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Preliminary Results on Safety and Activity of a Randomized, Double-Blind, 2 x 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in Premenopausal Women

Aliana Guerrieri-Gonzaga, Chris Robertson, Bernardo Bonanni, Davide Serrano, Massimiliano Cazzaniga, Serena Mora, Marcella Gulisano, Harriet Johansson, Franca Formelli, Mattia Intra, Antuono Latronico, Dorella Franchi, Giuseppe Pelosi, Karen Johnson, Andrea Decensi

From the Divisions of Chemoprevention, Breast Surgery, Breast Diagnostics, Gynaecologic Surgery, and Pathology, European Institute of Oncology; Chemoprevention Unit, National Cancer Institute, Milan; Division of Medical and Preventive Oncology, E.O. Ospedali Galliera, Genoa; Division of Medical Oncology, Ospedale S. Bortolo, Vicenza, Italy; Department of Statistics and Modelling Science, Strathclyde University, Glasgow, Scotland, United Kingdom; and Division of Cancer Prevention, National Cancer Institute, Bethesda, MD

Address reprint requests to Andrea Decensi, MD, Division of Chemoprevention, European Institute of Oncology, via Ripamonti, 435, 20141 Milan, Italy; e-mail: andrea.decensi{at}ieo.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
PURPOSE: To determine whether low-dose tamoxifen and fenretinide have a synergistic effect on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, in premenopausal women at risk for breast cancer and to study drug safety.

PATIENTS AND METHODS: Premenopausal women (n = 235) were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years. The present analysis refers to preliminary data on safety, IGF-I, and breast cancer events.

RESULTS: Patients were included if they had an excised ductal carcinoma-in-situ (57%), lobular carcinoma-in-situ (13%), minimal invasive breast cancer (7%), or a 5-year Gail risk ≥ 1.3% (23%). After a median follow-up of 40 months, there was a reduction of 13%, 2%, 20%, and 1% in IGF-I levels for patients on tamoxifen, fenretinide, tamoxifen plus fenretinide, and placebo, respectively. Recruitment was stopped based on the lack of an interaction on IGF-I levels, which was a primary end point for the study. Thirty-six patients have dropped out of the study, 17 because of adverse events and 19 for various other reasons. One stage I endometrial cancer occurred in a patient on fenretinide, and one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen. There was no difference in menopausal symptoms, endometrial thickness, polyps, or ovarian cysts among treatment arms. To date, 24 breast cancers have been observed, without differences among arms.

CONCLUSION: The combination of low-dose tamoxifen and fenretinide is safe but not synergistic in lowering IGF-I levels in premenopausal women. The clinical implications require further follow-up.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
The partial estrogenic activity of tamoxifen is a limiting factor in cancer prevention. Although the agonistic activity of tamoxifen reduces osteoporotic bone fractures,1 this property increases the risk of endometrial tumors,1,2 including uterine sarcomas,3 and venous thromboembolism.1,4 However, the risk of endometrial cancer related to tamoxifen is time and dose dependent.5 Moreover, it was shown in a preoperative trial that doses of 5 or 1 mg/d of tamoxifen had a similar antiproliferative effect on Ki-67 expression compared with the standard dose. Also, the two lower doses had fewer effects on circulating biomarkers of tamoxifen estrogenicity, including insulin-like growth factor I (IGF-I), sex hormone–binding globulin, low-density lipoprotein cholesterol, and antithrombin III.6

Retinoids have extensively been studied as preventive agents in breast cancer.7 In a phase III trial in nearly 3,000 women with stage I breast cancer, fenretinide administered for 5 years induced a 35% reduction in contralateral breast cancer and ipsilateral reappearance in premenopausal women.8 Fenretinide administration for 1 year in premenopausal women was also associated with a reduction of plasma IGF-I and an increase in IGF-binding protein 3 (IGFBP-3).9,10 In addition, high IGF-I and particularly low IGFBP-3 levels predicted second breast cancer risk.11 Higher IGF-I levels are associated with increased risk of premenopausal breast cancer in prospective studies,12-14 and tamoxifen at low doses reduces circulating IGF-I levels.15 Mammographic percent density assessed by computerized methods has also been associated with increased breast cancer risk in prospective studies,16,17 and its reduction for women under age 45 was observed in a primary prevention trial also showing reduction of cancer incidence for women on tamoxifen.18 These findings support the notion that circulating IGF-I and mammographic percent density may serve as surrogate end point biomarkers (SEBs) in phase II trials.19

Because the combination of tamoxifen and fenretinide is synergistic in rodent and cell line mammary tumor models and its tolerability has already been demonstrated in clinical trials,20-22 we conducted a clinical study in premenopausal women using the change over 2 years in plasma IGF-I and mammographic density as SEBs. This article is focused on safety data from that study, including endometrial and ovarian effects, as well as preliminary data on circulating IGF-I levels and breast cancer events.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Eligibility Criteria
Eligible patients were premenopausal women (last menstrual period within 6 months or follicle-stimulating hormone levels < 40 U/L if hysterectomized with ovary preservation) with either an in situ cancer or a small invasive cancer of favorable prognosis (pT ≤ 1 cm, N0, grade 1 or 2, Ki-67 < 20%, and estrogen receptor positivity ≥ 10% or unknown) in the previous 3 years. Unaffected women were eligible if they had a Gail 5-year risk for breast cancer of ≥ 1.3%. Other requirements were willingness to forgo pregnancy and the use of oral contraceptives. All patients signed a consent form approved by the local institutional review board. Criteria for exclusion were any prior chemotherapy or hormonal therapy for breast cancer; any malignancy (except carcinoma-in-situ and skin basal cell carcinoma); any retinal and ocular disorders; photodermatitis; stage III or IV endometriosis; ≥ grade 2 alterations of hematologic, liver, and renal function; hypertriglyceridemia; CNS diseases and major psychiatric diseases; and history of venous thrombo-embolism and transient ischemic attack. The study was conducted at the European Institute of Oncology, Milan, and at the Division of Medical Oncology, S. Bortolo Hospital, Vicenza, Italy.

Interventions and Study Procedures
A 2 x 2 factorial design was followed for this randomized, double-blind, placebo-controlled trial. Patients were randomly assigned to one of the following arms: (1) tamoxifen 5 mg/d (one tablet) and fenretinide placebo capsules; (2) tamoxifen placebo and fenretinide 200 mg/d (two 100-mg capsules); (3) tamoxifen 5 mg/d and fenretinide 200 mg/d; or (4) both placebos. A monthly 3-day interruption of fenretinide was introduced to allow the partial recovery of retinal storage. Women were treated for 2 years and observeded for an additional year on a semiannual basis and received a 7-month supply of study medication to be self-administered. Toxicity was evaluated at each visit using the National Cancer Institute Common Toxicity Criteria (version 2.0, revised March 23, 1998), with dose modifications applied accordingly. Although endometrial polyps are not included in the National Cancer Institute Common Toxicity Criteria, they were recorded as a specific adverse event (AE) because of the association with tamoxifen. Mammography, breast ultrasounds, breast fine-needle aspirates, and transvaginal ultrasounds were performed at baseline and once a year. In all cases of suspicious or doubtful transvaginal ultrasound (ie, endometrial stripe ≥ 8 mm), a saline infusion sonohysterography was performed to view the two endometrial layers. For research purposes, an endometrial Pipelle biopsy was performed at baseline and at month 24 in all participants giving consent. All procedures and biomarker measurements were repeated in the same phase of the menstrual cycle to reduce variability.

Assay Methods
Fasting blood samples for circulating IGF-I were collected and stored at –80°C until centrally assayed. Plasma IGF-I was determined on EDTA by chemiluminescent immunometric assay method (Nichols Institute Diagnostics, San Juan, CA). The assay was performed on the automatic instrument LIAISON (Diasorin SpA, Saluggia, Italy). A prior calibration study had shown a high correlation with the enzyme-linked immunosorbent assay method used in previous studies.11 The sensitivity of the test was 0.8 nmol/L, whereas the intra- and interassay coefficients of variation of our in-house pooled serum control sample were 5.4% and 8.2%, respectively. Plasma drug and retinol levels were measured at baseline and every 12 months to assess treatment compliance using the method previously described.23

Objectives
The main aim of the study was to test a synergistic interaction between tamoxifen and fenretinide on several SEBs related to premenopausal breast cancer risk. Because the trial is not completely finished, the present analysis is focused on safety, particularly on menopausal symptoms and at the gynecologic level, and preliminary data on IGF-I and breast cancer events.

Outcomes
The main outcome measures were the changes in IGF-I and mammographic percent density values from baseline to the end of treatment at 24 months. Additional outcome measures included all AEs, atypia in random periareolar fine-needle aspirates, endometrial thickness and proliferation (Ki-67 expression), endometrial polyps, uterine volume, size of the largest myoma, ovarian size, and number of ovarian cysts. Menopause-related effects were investigated using the Menopause Quality of Life Questionnaire.24 Although the study was not powered to show differences on breast cancer events, these were analyzed for safety reasons.

Sample Size
The primary focus in this trial was the interaction between tamoxifen and fenretinide on IGF-I, and the planned sample size was 300 patients (75 per arm), including an allowance for a 15% dropout rate. On the basis of literature data, assuming a baseline IGF-I value of 150 ± 45 ng/mL, we anticipated no effect with placebo, a 12% reduction with tamoxifen, a 22% reduction with fenretinide, and a 15% to 53% reduction with the combination arm. The standard deviation of the differences was assumed to be 35 ng/mL based on a correlation of 0.6 between baseline and end point IGF-I values. At the 5% significance level, with 65 patients per group, the study had 90% power to detect this interaction and 95% power and more than 99% power to detect the main effects of tamoxifen and fenretinide, respectively, in the absence of any interaction. Changes in mammographic percent density were also considered as a surrogate end point but will be published with the final results. To control for an overall 5% significance level, each of the two interaction tests was carried out at the 2.5% level. A Data Safety Monitoring Committee meeting was held annually. In the Data Safety Monitoring Committee meeting of April 2002, it was apparent that there was no synergistic effect on IGF-I. Because sufficient patients had been accrued to give a 92% and more than 99% power for testing the effects on IGF-I by tamoxifen and fenretinide alone, respectively, recruitment was stopped. Patients were informed about the early closure of accrual but were asked to continue treatment because no safety concern was evident.

Random Assignment
Random assignment was performed via a centralized phone call using permuted blocks of four, where women were assigned to one of the treatment groups. Patients were stratified by participating center and disease status (unaffected v affected). Study personnel and participants were blinded to treatment assignment for the duration of the study.

Statistical Analysis
Quantitative measurement variables, such as IGF-I, endometrial thickness, uterine volume, and ovarian size, were analyzed through a repeated-measures analysis of variance model at 6, 12, 18, and 24 months (through linear, quadratic, and cubic effects), adjusting for baseline value and strata. The treatment effects were the individual effects of tamoxifen and fenretinide and their interaction. A log transformation was used for IGF-I, endometrial thickness, uterine volume, myoma diameter, and ovarian size. For the gynecologic effects/events, a menstrual cycle category (days 1 to 14, days 15 to 40, or postmenopausal) was included in the statistical model together with interactions with the treatment effects, if necessary. Ovarian cysts were analyzed through a Poisson regression model, adjusting for baseline counts and time on study and menstrual cycle phase as covariate. AEs were analyzed according to the time to the first AE, with patients censored when they went off study. Breast cancer events were analyzed using the log-rank test to compare the time to event curves. Results were expressed as the mean ± standard deviation annual rate/100.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
As of February 2005, 235 patients had been randomly assigned; 19 patients (8%) refused to continue, 17 patients (7%) dropped out because of AEs/adverse drug reactions, 198 patients had completed treatment, and 180 patients had completed the additional year of follow-up. Baseline characteristics are listed in Table 1. Only 9% of the women had T1 tumors, whereas the majority of patients (68%) had ductal or lobular carcinoma-in-situ tumors.


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  		Table 1. Baseline Patient and Tumor Characteristics

 
Plasma levels of IGF-I during treatment are listed in Table 2. The analysis is based on nearly 220 assessable patients at 12 months. Mean baseline IGF-I levels were 140 ng/mL, with no significant difference among the four groups. Patients with a history of breast neoplasm showed a 10% higher mean IGF-I level compared with unaffected women (P = .07, data not shown). There was a 15% reduction of IGF-I levels on tamoxifen, which was already present after 6 months and did not change thereafter (P = .47 for the linear effect of time). From the repeated-measures analysis, there was a 14.6% reduction in IGF-I at all time points during treatment (P < .0001). Conversely, the reduction in IGF-I with fenretinide was approximately only 2% at each follow-up time. There was no interaction between drugs on IGF-I adjusting for baseline IGF-I levels using the repeated measures models (P = .71).


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  		Table 2. IGF-I Levels During Treatment

 
Mean (± standard deviation) plasma retinol levels on tamoxifen, fenretinide, both agents, and placebos were 575 ± 112, 565 ± 127, 553 ± 125, and 549 ± 126 ng/mL, respectively, at baseline and 541 ± 128, 231 ± 161, 260 ± 185, and 528 ± 145 ng/mL, respectively, at 12 months. The most frequent AEs are listed in Table 3. There was no significant difference in any AE or number of AE-related dropouts among the four arms. Of the three serious AEs, one stage I endometrial cancer occurred on fenretinide, whereas one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen.


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  		Table 3. Patients With Adverse Events or Reactions During Treatment

 
Mean endometrial thickness values at different time points are described in Table 4. The results are split into two subgroups according to menopausal status (patients who remained premenopausal v patients who became postmenopausal during intervention). The combination arm exhibited a trend to a decline in endometrial thickness similar to placebo, although there is no evidence of a significant interaction (P = .71). The repeated-measures analysis indicated that women becoming postmenopausal had a 47.0% (95% CI, 36.9% to 55.5%) thinner endometrial thickness than premenopausal women (P < .001), and the increase under tamoxifen was limited to women becoming postmenopausal (P = .002 for the interaction). A woman becoming postmenopausal and taking tamoxifen had an endometrial thickness that was 47.1% (95% CI, 16.1% to 86.5%) greater than a similar woman not taking tamoxifen. No difference in endometrial histology was observed among groups.


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  		Table 4. Endometrial Thickness in Women Remaining Premenopausal or Becoming Postmenopausal During Treatment

 
Uterine volume, which was calculated as the product of the three diameters divided by 2,25 showed some interaction between drugs. Specifically, tamoxifen had no effect (P = .36), fenretinide decreased uterine volume by 13.2% (95% CI, 1.6% to 23.5%), and fenretinide and tamoxifen increased uterine volume by 24.9% (95% CI, 4.7% to 48.9%) relative to tamoxifen alone or fenretinide alone. There were no significant differences in number and size of uterine myomas. A reduction in maximum diameter of the ovaries was observed in all women during the study as a result of aging. However, tamoxifen increased the maximum ovarian diameter compared with no tamoxifen, whereas fenretinide had no effect. Both drugs had no effect on ovarian cyst numbers (data not shown).

After a median follow-up of 40 months, 24 breast events have occurred (two lobular and six ductal carcinoma-in-situs and 16 infiltrating breast cancers). The annual rates of breast events are listed in Table 5. Fewer events were noted on tamoxifen or fenretinide compared with placebo or the combination arm, but the numbers are too small to attempt any reliable conclusion.


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  		Table 5. Annual Rate of Breast Neoplasms

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Tamoxifen is US Food and Drug Administration–approved for breast cancer risk reduction, but its prescription as a preventive drug is limited for a variety of reasons, including concerns about toxicity. New approaches have been proposed to improve the cost to benefit ratio, such as lowering the dose or adding aspirin to reduce the risk of venous thromboembolism.

A dose reduction of tamoxifen is supported by the results of a preoperative trial in 120 women,6 in which the change in Ki-67 expression induced by lower doses was equivalent to the standard dose. Conversely, circulating biomarkers of drug estrogenicity showed a dose-response relationship, suggesting reduced estrogenic effects of tamoxifen at lower doses, at least in postmenopausal women.6

In this phase IIb trial, we assessed the combination of tamoxifen 5 mg/d and fenretinide in 235 premenopausal women at-risk of breast cancer. Synergistic efficacy has been observed in animal studies,26-29 and the combination of these two drugs was well tolerated in pilot trials.30 However, an adjuvant trial of tamoxifen and fenretinide in postmenopausal women was stopped because of poor accrual and high dropout rate.31

Our study indicates that the combination of low-dose tamoxifen and fenretinide in premenopausal women is very well tolerated, with no evidence of increased AEs compared with placebo or either agent alone. Tamoxifen 5 mg/d for up to 2 years did not increase menopausal symptoms, including hot flashes, vaginal discharge, and night sweats. These results are important because large prevention trials have shown that tamoxifen 20 mg/d increases bothersome hot flashes and vaginal discharge two- to three-fold32 and that these symptoms are the most important reason for early withdrawal.33-35

Low-dose tamoxifen significantly increased endometrial thickness only in women becoming postmenopausal during the study, whereas the addition of fenretinide counteracted this effect. No excess of endometrial polyps or ovarian cysts was noted. In contrast, tamoxifen 20 mg/d increases endometrial thickness three-fold and causes polyps in approximately 10% to 15% of women after 2 to 3 years of treatment,36 possibly in a dose-dependent37 and time-dependent38 fashion. In the National Surgical Adjuvant Breast and Bowel Project P1 trial,32 the annual rate of polyps and ovarian cysts in premenopausal women increased from 13 to 25 and from 18 to 26 per 1,000 with tamoxifen 20 mg/d compared with placebo, respectively. In postmenopausal women, tamoxifen increased the incidence of polyps from nine to 21 per 1,000.32 Importantly, the increase in ovarian cysts in premenopausal women has been associated with higher estradiol levels and younger age,39 with a potential escape to treatment control.40 Because endometrial thickness is a surrogate for polyps and cancer,41,42 our findings suggest that tamoxifen 5 mg/d is safer than the standard dose, but further follow-up is necessary to confirm this conclusion.

Although fenretinide inhibits aromatase activity in vitro43 and blocks growth and induces apoptosis of leiomyoma cells,44 its effect modification at the uterine and endometrial level after adding tamoxifen is difficult to explain. In a previous trial,11 fenretinide exhibited a different effect on IGF-I levels and second breast malignancies depending on menopausal status or age, thus suggesting a hormonal modulation of its effects. Interestingly, retinoids and steroids cross talk at gene level as ligands of the nuclear receptor superfamily.45

Low-dose tamoxifen reduced plasma IGF-I levels by 15%, which is an effect that is comparable to the effect achieved with the standard dose. Baseline levels were higher in affected women compared with women at risk by the Gail model, which is in line with the association found in prospective studies in premenopausal women.13,14,46 In a previous study of fenretinide,46 a 13% and 11% durable decline of IGF-I and IGF-I:IGFBP-3 molar ratio, respectively, were associated with a 35% lower risk of second breast malignancies in premenopausal women.

In contrast to all previous studies,9,46 there was no reduction of IGF-I by fenretinide. We have no ready explanation for this surprising finding, which cannot be explained by lack of compliance because retinol concentrations declined to an extent similar to that reported in previous studies.23 The lack of an excess of AEs associated with fenretinide, such as diminished dark adaptation and dermatologic reactions, suggests that the drug used in this study may be less active, but we have no evidence to support this contention. Also, the efficacy of fenretinide in the phase III trial was only partially explained by its effect on the IGF system, so additional mechanisms may take place.

The rate of breast cancers in the placebo arm was comparable to previous studies in women with DCIS.47 Although the combination arm does not seem to decrease breast cancer events, both single agents showed a possible reduction. However, this observation has limited power, so further follow-up is necessary before any reliable conclusion can be made.

In conclusion, fenretinide had limited activity on IGF-I and no synergistic interaction with tamoxifen was noted. Treatment with tamoxifen 5 mg/d did not increase menopausal symptoms, had no adverse effects on endometrial and ovarian level, and decreased plasma IGF-I levels to an extent that has been associated with a risk reduction of premenopausal breast cancer. Therefore, further studies of low-dose tamoxifen are recommended.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
The authors indicated no potential conflicts of interest.


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 

Conception and design: Chris Robertson, Andrea Decensi

Financial support: Andrea Decensi, Karen Johnson

Administrative support: Aliana Guerrieri-Gonzaga, Serena Mora, Andrea Decensi

Provision of study materials or patients: Bernardo Bonanni, Davide Serrano, Massimiliano Cazzaniga, Marcella Gulisano, Harriet Johansson, Franca Formelli, Mattia Intra, Antuono Latronico, Dorella Franchi, Giuseppe Pelosi, Andrea Decensi

Collection and assembly of data: Aliana Guerrieri-Gonzaga, Bernardo Bonanni, Davide Serrano, Massimiliano Cazzaniga, Serena Mora, Marcella Gulisano, Harriet Johansson, Antuono Latronico, Andrea Decensi

Data analysis and interpretation: Aliana Guerrieri-Gonzaga, Chris Robertson, Bernardo Bonanni, Karen Johnson, Andrea Decensi

Manuscript writing: Aliana Guerrieri-Gonzaga, Chris Robertson, Karen Johnson, Andrea Decensi

Final approval of manuscript: Aliana Guerrieri-Gonzaga, Chris Robertson, Bernardo Bonanni, Davide Serrano, Massimiliano Cazzaniga, Marcella Gulisano, Harriet Johansson, Mattia Intra, Antuono Latronico, Dorella Franchi, Giuseppe Pelosi, Karen Johnson, Andrea Decensi

 


   ACKNOWLEDGMENTS
 
Fenretinide and tamoxifen were given as gifts by RW Johnson Pharmaceutical Research Institute, Spring House, PA and by Laboratori MAG, Garbagnate, Italy, respectively. The Data and Safety Monitoring Committee included Marc E. Lippman, MD, Ann Arbor, MI; Richard D. Gelber, Boston, MA; and Trevor Powles, MD, London, United Kingdom.


   NOTES
 
Supported by National Cancer Institute grant No. CA-77188, a contract from the Italian Foundation for Cancer Research, and regional grant No. 1068/2005 on second tumors from the Associazione Italiana per la Ricerca sul Cancro.

Presented in part at the American Association for Cancer Research Prevention Meeting, Phoenix, AZ, October 26-30, 2003; and at the 40th Annual American Society of Clinical Oncology Meeting, New Orleans, LA, June 5-8, 2004.

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


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
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Submitted June 16, 2005; accepted October 13, 2005.




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