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© 2000 American Society for Clinical Oncology Pilot Trial of the Safety, Tolerability, and Retinoid Levels of N-(4-hydroxyphenyl) Retinamide in Combination With Tamoxifen in Patients at High Risk for Developing Invasive Breast CancerFrom the Greenebaum Cancer Center, Divisions of Hematology and Oncology, and Department of Medicine, University of Maryland School of Medicine, Baltimore; Medicine Branch, Laboratory of Pathology, and Surgery Branch, Division of Clinical Sciences, National Cancer Institute (NCI); Pharmacy Department, Department of Radiology, Warren Grant Magnusen Clinical Center; and National Eye Institute, National Institutes of Health, Bethesda, MD. Address reprint requests to JoAnne Zujewski, MD, Medicine Branch, Rm 12N226, Bldg 10 (Clinical Center), NCI, NIH, 9000 Rockville Pike, Bethesda, MD 20892; email zujewski{at}nih.gov
PURPOSE: N-(4-hydroxyphenyl) retinamide ([4-HPR], Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer. PATIENTS AND METHODS: Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated.
RESULTS: Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P CONCLUSIONS: TAM administration did not affect Cp 4-HPR or 4-MPR. Reversible nyctalopia correlated with relative decrease in Cp retinol but was not symptomatic for most patients. TAM + 4-HPR has acceptable tolerability for this high-risk cohort.
TAMOXIFEN (TAM), a nonsteroidal antiestrogen, is associated with a 35% to 50% decreased incidence of contralateral breast cancer when used as adjuvant therapy after initial curative surgery.1 Recently, TAM administration has also been found to decrease the risk of developing breast cancer in women at high risk for this disease.2 The mechanism of action of TAM is presumed to be through its competitive inhibition of estrogen binding to the estrogen receptor (ER). However, it may also perturb tumor growth, or carcinogenesis, through non-ER–mediated pathways.3
Retinoids have also been shown to inhibit tumor growth and induce differentiation in a variety of experimental models. All-trans-retinoic acid (ATRA) has been shown to inhibit growth of ER-positive breast cancer cells, but not ER-negative cancer cell lines.4 Retinoids are presumed to exert their activity via retinoic acid receptors (RARs), although the exact pathways have not been elucidated to date. Transfection of RAR
N-(4-hydroxyphenyl) retinamide ([4-HPR], Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) is a semisynthetic retinoid that does not bind well to RAR In a large Italian trial of 4-HPR in women with surgically treated early-stage breast cancer, the agent was well tolerated. Reversible, symptomatic nyctalopia was observed in approximately 10% of patients.14,15 There was a suggestion that the incidence of nyctalopia is dose-related.14 4-HPR has been shown to lower plasma concentrations of both retinol and retinol-binding protein.16 Decensi et al 17 correlated plasma retinol concentrations (Cp) below 160 ng/mL with moderate alterations in the Goldmann-Weekers dark adaptometry test. The same group described patient age older than 55 years, high percentage of adipose tissue, and higher plasma concentration of the 4-HPR metabolite N-(4-methoxyphenyl) retinamide (4-MPR) as risk factors for severe decrease in retinol Cp.18 In clinical studies, 4-HPR (300 to 400 mg/d) had no activity in a phase II trial in patients with advanced or metastatic breast cancer.19 However, minor responses or disease stabilization was reported in 12 of 15 previously untreated patients with metastatic breast cancer treated in a phase I/II trial with the combination of TAM and 4-HPR.20 These results suggest that the activity of the combination may be greater for early or precancer than for advanced or metastatic disease. Preliminary results from a large randomized trial of 4-HPR versus no intervention in women with surgically treated stage I breast cancer suggested that 4-HPR may be effective in reducing the local recurrence and contralateral breast cancer rates in premenopausal women.21 Although plasma concentrations of 4-HPR and its active metabolite, 4-MPR, have been studied after the administration of 4-HPR as a single agent,18,22 there has been no assessment, to date, of the effect of TAM, if any, on the incidence and severity of clinical toxicity or plasma concentrations of 4-HPR or 4-MPR. However, treatment of mice with phenobarbital, an inducer of cytochrome P450 enzymes, has resulted in lower concentrations of 4-HPR and metabolites in the rodent.23 TAM may also be metabolized, in part, by the cytochrome P450 mixed function oxidase system24-26 and, therefore, may affect plasma concentrations of 4-HPR and its metabolites. The synergistic effects of TAM and 4-HPR in combination in preventing mammary tumors in preclinical models, the efficacy of TAM in reducing the risk of invasive breast cancer, and the preliminary results suggesting that 4-HPR may be effective in reducing the risk of contralateral breast cancer in premenopausal women, make TAM and 4-HPR an attractive combination for chemoprevention. We performed the first pilot chemoprevention trial of this combination of 4-HPR and TAM in women at high risk for development of invasive breast cancer to assess the tolerability of the combination, document any associated toxicities, test the feasibility of collecting multiple samples longitudinally for assessment of surrogate biomarkers of malignancy, and assess the effect of TAM on steady-state plasma concentrations of 4-HPR and 4-MPR. Because this drug combination was being tested in a healthy population and because toxicity data on long-term administration of TAM + 4-HPR was limited, the trial was designed to administer 4-HPR alone for the initial 25 days, followed by the combination of 4-HPR and TAM for the subsequent 3 months, and then TAM alone for an additional 20 months (2-year total treatment). This design also allowed for assessment of steady-state plasma concentrations of 4-HPR and 4-MPR with and without concurrent TAM. A 200-mg dose of 4-HPR daily was chosen because it had been found to be tolerable in a similar cohort of patients and because it produces serum concentrations of 4-HPR in the range of those found to be effective in vitro. 7,22
Patients Patients were eligible for the study who were at least 35 years of age and were at high risk of developing invasive breast cancer, defined as (1) a histologically documented diagnosis of ductal carcinoma-in-situ, with or without microinvasion, and treated by standard therapy (lumpectomy and radiation or mastectomy); (2) a histologically documented diagnosis of lobular neoplasia (including atypical lobular hyperplasia or lobular carcinoma-in-situ); (3) atypical ductal hyperplasia in a postmenopausal woman or in a premenopausal woman with a positive family history of breast cancer; or (4) a high-risk family history, defined as breast cancer or ovarian cancer diagnosis in at least three first- or second-degree relatives (at least one of these relatives must have had breast cancer), or at least two first-degree relatives with breast cancer diagnosed under the age of 50 years, or at least one first-degree relative with breast cancer and at least one case of ovarian cancer in the extended pedigree. Patients must have had no concurrent malignancy, cervical carcinoma-in-situ, or any other malignancy within 5 years of study entry. Eligible patients had normal hepatic, renal, and hematopoietic function. All subjects had normal gynecologic examinations before study entry. All subjects were ambulatory, with good performance status (Eastern Cooperative Oncology Group status 0 to 1) and a life expectancy of at least 10 years. All subjects signed an informed consent approved by the Institutional Review Board at the National Cancer Institute. All fertile, sexually active women were informed of possible risks to the fetus and signed a separate consent in which they agreed to use effective, nonhormonal birth control methods for at least 2 months after the end of TAM and at least 12 months after the end of 4-HPR treatment. Patients with a history of bleeding disorder or abnormal coagulation studies, prior history of deep venous thrombosis or pulmonary embolus, abnormal vaginal bleeding, prior retinal disease, macular degeneration or night blindness (nyctalopia), uncontrolled medical or psychiatric illnesses, concurrent hormonal use, or who were pregnant or nursing were excluded from study participation.
Treatment Regimen
Pretherapy Evaluation and Follow-Up Follow-up evaluations were performed every 2 weeks initially, then every 4 weeks during the 4-HPR treatment, then every 3 to 6 months. Evaluations included blood studies (complete blood cell count, liver function panel, electrolytes, and lipid profile). At 1, 4, and 6 months, and every 6 months to the end of the study, a history, physical examination, and toxicity evaluation were performed. Transvaginal ultrasound with measurement of endometrial thickness was repeated at 4, 12, and 24 months. Mammography and gynecologic examinations were repeated yearly.
Ophthalmologic Toxicity Assessment
Tissue Acquisition
Retinoid Cp High-performance liquid chromatography analysis. Retinoid concentrations in plasma were determined by reversed-phase gradient high-performance liquid chromatography with a modification of the method of Bugge et al.28 Briefly, 500 µL of plasma, containing 70 nmol/L Ro-11-5036 (Hoffmann-LaRoche Inc, Nutley, NJ) as internal standard, were extracted with acetonitrile:1-butanol (50:50, vol/vol) in the presence of KH2PO4 (1 kg/L), pH 11.08. The samples were centrifuged and the organic phase was analyzed by high-performance liquid chromatography using a Beckman 506A autosampler (Beckman Instruments, Inc, San Ramon, CA) and a Zorbax ODS special analytic C-18 column with no end-capping (MacMod Analytic, Chadds Ford, PA), 25 cm x 4.6 mm internal diameter, containing five micron spherical particles. Mobile phase A consisted of acetonitrile:0.02 mol/L ammonium acetate:acetic acid (50:50:0.5 by volume), pH 4.6. Mobile phase B consisted of acetonitrile:0.2 mol/L ammonium acetate:acetic acid (95:5:0.4 by volume), pH 8.4. Retinoid peaks were detected at 360 nm with a Beckman model 406 variable wavelength detector. With these conditions, good baseline separation of compounds was achieved, with retention times of approximately 10.6, 12.5, 15.4, 14.8, and 16.5 minutes for internal standard, 4-HPR, retinol, ATRA, and 4-MPR, respectively. No endogenous plasma peaks interfered with the determination of the compounds of interest. Concentrations were determined with reference to a concomitantly performed standard curve. Because the peak absorption wavelength for retinol is 325 nm, determination of retinol concentration required modification of the assay to this wavelength. The assay was linear between 0 and 1 µmol/L 4-HPR and 4-MPR and between 0 and 1000 ng/mL retinol. Intraday and interday coefficient of variation percent was approximately in the range of 5% to 15%. Samples outside the linear range were diluted and assayed again.
Statistical Analysis Serum cholesterol, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein values were compared at baseline, after cycle 1 (4-HPR only), after cycle 4 (4-HPR and TAM), and after 1 year (TAM alone). Changes in HDL level, cholesterol level, and triglyceride level were assessed using the Wilcoxon signed rank test. The distribution of triglyceride levels was highly skewed, and these levels were logarithmically transformed before being tested.
Patients and Treatment Thirty-two women entered onto the trial. Patient characteristics are listed in Table 1. All patients were treated between August 1994 and June 1998. A total of 555 cycles (months) of therapy were administered: 32 cycles of 4-HPR alone, 85 cycles of 4-HPR in combination with TAM, and 438 cycles of TAM alone. The median age of the patients was 49 years (range, 37 to 74 years). Fifty-nine percent of the patients were postmenopausal. Most entered the study with known proliferative breast disease on biopsy. Seventeen patients completed 24 months of treatment, and nine patients continue on study. Six patients did not complete all treatment. Twenty-eight of 32 patients completed at least 4 months of therapy.
Toxicity Toxicities of the treatment were generally mild (Table 2). Six patients did not complete the treatment regimen. Four women discontinued participation because of side effects: one for grade 1 nausea; one for a grade 2 skin rash; one for hot flashes, weight gain, and nausea; and one for atypical migraines, manifesting as temporary loss of vision. Two additional patients discontinued trial participation for reasons unrelated to drug toxicity. One patient developed ductal carcinoma-in-situ, and one patient had exacerbation of pre-existing multiple sclerosis (optic neuritis).
The most prominent toxicities encountered were hot flashes in 84% of patients and ophthalmologic symptoms in 21 patients (dry eyes in 17 patients). Mild skin dryness, fatigue, and mood changes were also commonly reported by patients. Seven patients required therapy with antidepressants during the course of the study. Several symptoms were first observed during the month that 4-HPR was administered alone: abdominal pain (four of six patients); nausea (five of eight patients); arthralgia/myalgia (three of five patients); and vomiting (two of two patients). In the majority of cases, these symptoms resolved either before or with cessation of 4-HPR. In contrast, mood alterations were first reported after TAM was begun, either during administration with 4-HPR (eight patients), or during TAM therapy alone (nine patients). Vaginal symptoms were also first reported after TAM was begun, either during administration with 4-HPR (five patients) or during TAM therapy alone (nine patients). Fatigue was first reported with 4-HPR alone in two patients, during TAM in combination with 4-HPR in 12 patients, or during TAM therapy alone in three patients. There were no significant liver function abnormalities. One patient was diagnosed with Crohn’s disease, and one patient was diagnosed with giant cell arteritis while on study. These conditions were not thought to be related to study drug. Two patients (6%) had symptomatic nyctalopia. Two other patients had transient symptoms that may have been related to impaired dark adaptation. Rod-cone break delay above the upper limits of normal (6.92 minutes) was observed in 16 of 22 patients tested. The two patients with sustained symptomatic nyctalopia had delays of 8.21 and 13.04 minutes.29 All patient visions and rod-cone break delays returned to baseline after 4-HPR was discontinued, even though TAM treatment continued. Four patients were noted to have cataracts; one of these patients had cataract surgery while on study. Summary data for HDL, cholesterol, and triglycerides are presented in Table 3. Comparisons were made between baseline and the end of cycle 1 (4-HPR alone), between baseline and cycle 4 (combined therapy), and between baseline and year 1. Two significant changes were observed. An increase of serum HDL was noted by cycle 4, but not, interestingly, at year 1, implying that 4-HPR in combination with TAM may have a salutary effect on this cardiovascular risk factor. Also, a decrease in total cholesterol from baseline to month 4 was observed. This decrease was also apparent at year 1. This is consistent with other reports demonstrating a cholesterol-lowering effect of TAM.
Cp Retinol and Pharmacodynamic Assessment Retinoid Cps at baseline, after 1 and 4 months of 4-HPR treatment, and after 12 months on study are listed in Table 4. Baseline Cp retinol ranged from 296 to 1,433 ng/mL, with a mean ± SD of 708 ± 280 ng/mL. The observed decline in retinol concentrations is relatively stable after 1 month of 4-HPR treatment and recovered to baseline by 12 months on study (8 months after the end of 4-HPR administration). Mean decrease in plasma retinol concentration from baseline to month 4 was 60% (range, 21% to 80%).
There was considerable interpatient variability in the Cp 4-HPR and 4-MPR. For example, for month 4, Cp 4-HPR ranged from 0.15 to 1.11 µmol/L, and Cp 4-MPR ranged from 0.15 to 0.7 µmol/L. The mean concentrations of 4-HPR and 4-MPR were similar after 1 month of 4-HPR alone and after 3 months of 4-HPR + TAM (Table 4). There were four patients who seemed to have a large increase in Cp 4-HPR after the addition of TAM. The largest increase was in patient no. 8, who had a 4-HPR Cp of 0.21 µmol/L after 1 month of 4-HPR alone but a 4-HPR Cp of 1.11 µmol/L after 3 months of the combination. The largest decrease in Cp 4-HPR was in patient no. 12, who had a 4-HPR Cp of 1 µmol/L after 1 month of 4-HPR alone and a Cp 4-HPR of 0.05 µmol/L after 3 months of the combination. There was a significant correlation between the relative decrease in Cp retinol and rod-cone break delay, which has been previously reported.29
Tissue Acquisition Tissue samples obtained were examined for pathologic diagnosis. One patient was diagnosed with ductal carcinoma-in-situ after a mammographically guided biopsy of an area of changing calcifications observed after 9 months on study. The remaining biopsies were benign, with only one patient demonstrating atypical ductal hyperplasia on a core biopsy obtained for research purposes
TAM and 4-HPR are an attractive combination for the chemoprevention of breast cancer. 4-HPR and TAM was administered in combination with acceptable toxicity to this high-risk population. Six percent of our patients had symptomatic reversible nyctalopia, which is a similar incidence to that reported by others.16,17,19-22,30 The high incidence of hot flashes in our trial is consistent with that found in the trial of TAM alone in women at high risk of breast cancer reported by the National Surgical Adjuvant Breast and Bowel Project (NSABP).2 In that trial, 82% of 6,466 patients experienced some degree of hot flashes, whereas 84% (27 of 32) of patients in our trial reported hot flashes (Table 2). Other trials using TAM as a chemopreventive reported hot flashes in up to 33% of patients.31-33 Other toxicities were reversible and mostly low-grade, although approximately 20% of women dropped out of the trial even with low-grade toxicities. This drop-out rate is similar to the drop-out rate reported by the NSABP in their prevention trial.2 In that study, 21.6% of patients discontinued assigned therapy for reasons not specified in the protocol, 19.7% of the placebo group, and 23.7% of the TAM group. The toxicities observed in our study with the combination are similar to that reported with TAM and 4-HPR as single agents. Gastrointestinal side effects were first reported most frequently with 4-HPR therapy alone and resolved either before or with the cessation of 4-HPR. Hot flashes, vaginal discharge, menstrual changes, or mood alterations first occurred with TAM administration either in combination with 4-HPR or after TAM discontinuation. In the NSABP prevention study,2 hot flashes and vaginal discharge were noted to be more frequent in the TAM-treated group than in the placebo group. There was no difference noted between the TAM and the placebo group using a self-administered depression scale developed by the Center for Epidemiologic Studies. However, depression was not uncommon, with approximately 35% of patients scoring above 15 in that scale and 9% of patients scoring above 30. Interestingly, the combination of 4-HPR and TAM was associated with a lowering of serum cholesterol and an increase in serum HDL levels. The effects on HDL did not persist during the treatment with TAM alone. Other studies have reported favorable effects on total cholesterol and low-density lipoprotein cholesterol with TAM treatment. However, in the majority of these studies, HDL levels were either unchanged or slightly reduced.34-38 There was no effect of 4-HPR treatment or the combination treatment of 4-HPR and TAM on serum triglyceride levels, in contrast to hypertriglyceridemia observed with the administration of other retinoids.39 If sustained over longer periods of administration, the cholesterol lowering and HDL increase noted in patients treated with the combination of 4-HPR and TAM, if validated, may lower risk for coronary artery disease. Our data on the decrease in Cp retinol and its stability after 1 month of 4-HPR therapy are consistent with those reported by Formelli et al, 22 who studied patients receiving 4-HPR alone for 5 years. Taken together, these findings and the clinical findings imply that TAM does not significantly alter the pharmacodynamic effects or the retinol-lowering effect of 4-HPR, at least in the short term. Our trial design allowed measurement of 4-HPR, 4-MPR, and retinol after 1 month of 4-HPR alone, as well as after 3 months of 4-HPR administered with TAM. The mean concentrations of retinoids did not change with the addition of TAM, indicating no interaction in drug elimination. A minority of our patients had a large increase in both 4-HPR and 4-MPR Cps during the 3 months of treatment with 4-HPR and TAM compared with 4-HPR and 4-MPR Cps after 1 month of 4-HPR treatment alone. This variation could be caused by individual variation in elimination for 4-HPR, variation in the absorption of 4-HPR, or variations in the time of last medication. The fat content of meals can affect the amount of 4-HPR absorbed,40 and variation in the fat content of the diet may account for some of the variability observed. An effect of TAM on 4-HPR absorption (increase) or elimination (decrease) cannot be ruled out for those patients, but individual variation of this magnitude is not unusual and is supported by the wide range 4-HPR concentrations during month 1 (Cp 4-HPR range, 0.1 to 1 µmol/L) and month 4 (Cp 4-HPR range, 0.1 to 1.1 µmol/L; Cp 4-MPR range, 0.1 to 0.7 µmol/L). Formelli et al21 reported that 4-HPR and 4-MPR Cps remained stable throughout a 5-year treatment with 4-HPR and that 4-HPR Cps were approximately 1 µmol/L at a mean of 14 hours (range, 12 to 19 hours) after the last dose. Our data show lower trough concentrations of 4-HPR and 4-MPR, which could reflect differences between the two trials in sampling time relative to drug ingestion (in our trial, samples were obtained approximately 24 hours after dosing) and/or relative to the timing and fat content of food intake.
Relative decreases in Cp retinol from baseline were correlated with changes in dark adaptation. We found no correlation between Cps of 4-MPR and abnormalities in dark adaptation or between abnormal rod-cone break delay and Cp retinol Currently, the only definitive chemoprevention trial end point is the incidence of cancer. However, it is not feasible to take every potential chemopreventive agent into large, randomized clinical trials. Therefore, rational clinical evaluation of potential chemoprevention agents will require the identification and validation of relevant surrogate end point biomarkers. A necessary step in this process is to evaluate the feasibility of obtaining adequate tissue for these biomarker studies from a healthy population. In this study, we were able to demonstrate that tissue collection over 2 years was feasible, with adequate tissue for analysis obtained for the majority of patients. A review of models for early chemoprevention trials in breast cancer and a discussion of potential surrogate molecular markers has recently been published.41 Some potential candidates include the modulation of growth factors and their receptors (transforming growth factor beta, insulin-like growth factor-1, epidermal growth factor receptor modulation of the receptors for selective ER modulators or retinoids [level of expression of ER, progesterone receptor, or the RARs], markers of proliferation [Ki67 and proliferating cell nuclear antigen], and markers of genetic instability [loss of heterozygosity and p53 mutation]). Although we were able to obtain breast tissue for these studies, the amount of breast tissue obtained in a core needle biopsy is limited. Therefore, we are testing candidate markers for modulation after chemopreventive treatment in mammary tissues obtained from studies using methylnitrosourea carcinogen-exposed Sprague Dawley rats before testing these markers on human tissues. We are currently studying the modulation of transforming growth factor beta, a negative growth regulator42 that has been shown to be upregulated after TAM43 and retinoids,44 in this system. In conclusion, short-term (3 months) administration of TAM and 4-HPR is tolerable in this cohort of patients. Toxicity was mild, and frequent toxicities included mucocutaneous and ocular dryness, hot flashes, and mood changes. Our data suggest a salutary effect of 4-HPR administration on serum cholesterol and HDL levels, which should be confirmed. There was no adverse effect on serum triglyceride levels. There was no evidence that TAM affected 4-HPR pharmacokinetics or that either drug affected toxicity of the other. The effect of longer term administration of 4-HPR + TAM on dark adaptation, development of symptomatic nyctalopia, persistence of hot flashes, retinol Cps, or other toxicities remains unknown. However, given the encouraging preclinical data, toxicity of 4-HPR + TAM administered for longer periods should be assessed.
We thank the following persons for their help in completing this trial: Caroline Barnes; Steven Lemon, MD; Andrea Abati, MD; Richard Lopchinsky, MD; Craig Shriver, MD; Ken Miller, MD; and Michele Gossard.
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Glick AB, McKune BK, Abdulkarem N, et al: Complex regulation by retinoic acid in the vitamin A-deficient rat. Development 111:1081-1086, 1991 Submitted January 15, 1999; accepted August 13, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
.01). Four patients stopped treatment for side effects, and 84% of patients had hot flashes. Other commonly reported (grade 
into ER-negative cells results in the cells becoming sensitive to the inhibitory effects of ATRA.
.
