Annals of Oncology Advance Access originally published online on January 10, 2006
Annals of Oncology 2006 17(5):813-817; doi:10.1093/annonc/mdj131
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© 2006 European Society for Medical Oncology
Bortezomib (VELCADE®) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits
1 Departments of Breast Medical Oncology, 2 Hematopathology, 3 Pathology, 5 Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX; 4 Millennium Pharmaceuticals Inc., Cambridge MA, USA
* Correspondence to: Dr M. Cristofanilli, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1354, Houston, TX 77030, USA Tel: +1 713 792 2817; Fax: +1 713 794 4385. E-mail: mcristof{at}mdanderson.orgb
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: Bortezomib (VELCADE®) is a potent inhibitor of the 26S proteasome with broad antitumor activity. We performed a phase II study of bortezomib to evaluate its clinical effects in patients with metastatic breast cancer.
Patients and methods: Twelve patients with metastatic breast cancer were treated with bortezomib (VELCADE®) at a dosage of 1.5 mg/m2 administered biweekly for 2 weeks with 1 week of rest in a 21-day cycle. The primary objective was clinical response rate. Toxicity and pharmacodynamics data were also obtained.
Results: No objective responses were observed. One patient had stable disease, and 11 others experienced disease progression. The median survival time was 4.3 months (range, 0.9–37 months). The most common grade 3 or 4 toxicities included fatigue (58%; n = 7) and skin rash (33%; n = 4). The mean inhibition of specific chymotryptic activity was 53.1% (± 13.33%). A statistically significant reduction in the plasma interleukin-6 level was seen (P = 0.0354).
Conclusion: Bortezomib was well tolerated but showed limited clinical activity against metastatic breast cancer when used as a single agent. The future development of this agent for the treatment of breast cancer should be guided by in vivo models that optimize activity in combination with other antitumor agents.
Key words: bortezomib, Velcade, breast cancer, proteasome inhibitor
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Breast cancer is the most common malignancy in women, accounting for >30% of all new cancers among women in the United States, with approximately 212 000 new cases and more than 40 000 deaths projected for 2005 [1
]. Improved screening for breast cancer has resulted in the detection of more localized disease, but in 6–10% of patients, the disease has already metastasized at the time of their initial diagnosis [2]. Moreover, 20–30% of patients with early stage disease eventually experience progression to metastasis. Currently available treatments are unable to eradicate metastatic cancer [3], and median survival for these patients is only 2–4 years [4, 5]. Improving the survival rates for metastatic disease has been the subject of intense investigation, and new agents and strategies are actively being evaluated.
Bortezomib (PS-341 or VELCADE® [Millennium Pharmaceuticals, Inc., and Johnson & Johnson Pharmaceutical Research & Development, LLC]) is a dipeptidyl boronic acid that is a highly selective and potent inhibitor of the 26S proteasome. The ubiquitin-proteasome protein degradation pathway plays an essential role in the orderly proteolysis of intracellular proteins. In cancer cells, this pathway affects numerous activities that are important for tumor development [6]. Preclinical studies have shown that bortezomib has broad antitumor activity, and numerous clinical trials are currently investigating its efficacy as a single agent and in combination with other active antitumor agents against a variety of malignancies [7–9]. Here we report the results of a phase II trial of bortezomib in patients with metastatic breast carcinoma to evaluate its efficacy, toxicity, pharmacodynamic and biologic activities.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patient recruitment
Twelve patients were enrolled from January 7, 2002, to November 10, 2003 in this single-institution phase II trial. Inclusion criteria included a diagnosis of metastatic breast carcinoma with measurable disease. Measurable disease was defined as a tumor either >20 mm in diameter identified by conventional computed tomography or a tumor >10 mm in diameter identified by spiral computed tomography in at least one dimension. Previous exposure to anthracycline and/or taxane either as an adjuvant treatment or for advanced disease was mandatory. However, patients may have received no more than one chemotherapy treatment following the diagnosis of metastatic disease. Additional eligibility requirements included age
18 years, an adequate performance status, a life expectancy of >12 weeks, and normal organ and marrow functions.
study design
The trial was approved by M. D. Anderson's institutional review board and by the Cancer Therapy Evaluation Program of the National Cancer Institute (CTEP/NCI). The primary objective of the trial was to evaluate the clinical efficacy of bortezomib in metastatic breast carcinoma on the basis of objective tumor response (complete response [CR] + partial response [PR]). The trial was designed according to Simon's two-stage design, with an interim analysis after the first 12 patients. If two or more objective responses were observed, the trial was to continue to enrol a maximum of 35 patients. All patients who received any dose of bortezomib were to be included in the response rate calculation. Patients were also to be followed until disease progression or death.
Because no patients experienced a CR or PR, we have analyzed only overall survival and progression-free survival. Overall survival (OS) time was measured from the start of treatment to the date of the last follow-up or death from any cause. Progression-free survival (PFS) time was measured from the start of treatment to the date of disease progression, death from any cause, or termination of treatment due to toxicity.
dosage and treatment schedule
Bortezomib was supplied by Millennium Pharmaceuticals (Cambridge, MA), through CTEP/NCI. One treatment cycle consisted of bortezomib administered as an intravenous bolus at a dosage of 1.5 mg/m2 biweekly for 2 consecutive weeks (on days 1, 4, 8 and 11 of a 21 day schedule) followed by 1 week of rest.
Patients were evaluated by clinical examination every 3 weeks and by conventional imaging techniques for response every 6 weeks using one-dimensional measurements as specified in the Response Evaluation Criteria in Solid Tumors guidelines [10]. Adverse events were scored using the descriptions and grading scales of the NCI's Common Toxicity Criteria software, version 2.0. Bortezomib administration was withheld in patients who experienced grade 3 hematologic or hepatic toxicity or any other grade 2 or greater nonhematologic toxicity. In the event of a grade 4 hematologic toxicity and/or grade 3 nonhematologic toxicity, the bortezomib was reduced one dose level, from 1.5 mg/m2 to 1.3 mg/m2. If a second dose reduction was required, bortezomib was reduced from 1.3 mg/m2 to 1 mg/m2. Patients requiring more than two dose-level reductions were withdrawn from the trial.
proteasome activity
Inhibition of proteasome activity in peripheral whole blood was determined using previously described methods [11]. Briefly, blood specimens were collected just before bortezomib was administered and then 1 h after treatment. Plasma was prepared from whole blood, and shipped to Millennium Pharmaceuticals, Inc. in dry ice for analysis. The percentage of proteasome activity inhibition was calculated by comparing the results of the pretreatment specimens with those of the 1-h post treatment specimens using the ratio of chymotryptic to tryptic activity (ChT:T) or by specific chymotryptic activity levels of the proteasomes (SpA) as determined by fluorogenic kinetic assay [11].
biomarker studies
Plasma samples were obtained from six patients before and after a 1-h bortezomib treatment and analyzed for the presence of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12 p70, and tumor necrosis factor (TNF)-
by using the Cytometric Bead Array according to manufacturer's instructions (BD-Pharmingen, San Diego, CA).
statistical methods
Estimates of time to disease progression and overall survival were calculated using the Kaplan-Meier method, with 95% confidence intervals indicated. The median follow-up time was the median observation time for all the patients. The Kaplan-Meier product limit method was used to estimate overall survival and progression-free survival rates. Analyses were done using S-Plus software, version 6.1 (Insightful Corporation, Seattle, WA).
Comparisons of plasma levels of the cytokine biomarkers were done using a nonparametric Mann-Whitney test to detect any statistical difference between the levels before and after bortezomib treatment.
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results |
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patients' characteristics
The characteristics of the 12 patients enrolled in this trial are listed in Table 1. The median age was 53 years (range, 30–72 years). Ten patients had previously undergone surgical resection of their tumor; two patients did not undergo surgery because of metastasis or a diagnosis of inflammatory carcinoma at presentation. In addition, ten patients had previously received anthracycline-based systemic therapy (as either neoadjuvant or adjuvant chemotherapy, including one patient treated with high-dose chemotherapy), but only one patient had received systemic therapy for metastatic disease prior to study enrolment. Four patients had anthracycline and taxane-refractory or resistant disease. The median time to progression before study enrolment was 23 months (range 0–84 months). Nine (75%) of the 12 patients had metastatic disease at multiple sites.
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treatment administered
The median duration of treatment for the 12 patients was 52.5 days (range, 11–110 days), and the mean number of cycles administered was 2.5 (range, 1–5 cycles). A total of 109 bortezomib treatment doses were administered. Five doses were held due to toxicities.
response and survival
No objective responses were observed among the 12 patients treated at the intent-to-treat analysis with median follow-up of 4.6 months (range: 0.9–37 months) (Table 2). One patient experienced disease progression before completion of the first course of treatment, and she was unable to return to the clinic for evaluation and confirmation of her disease. One patient's disease was stable for five cycles of treatment, and her time to disease progression was 3.5 months. The median overall survival time was 4.3 months (range, 0.9–12.5 months). Figure 1 shows the Kaplan-Meier curve for overall patient survival: nine patients died within their first 12 months of treatment, and the survival rate was 25% (95% CI, 9%–67%). The median time to progression was 1.6 months (range, 0.3–3.6 months). Figure 2 shows the Kaplan-Meier curve for progression-free survival of the patients.
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toxicity
The most common non-hematologic toxic effects noted with bortezomib treatment were fatigue, sensory neuropathy, nausea, and rash/desquamation (Table 3). The most common grade 3 or 4 nonhematologic toxicities were fatigue, rash and emesis.
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The most common hematologic toxic effects included thrombocytopenia and anemia; one patient experienced grade 4 thrombocytopenia with her last course of treatment and was withdrawn from the study because her disease progressed before a dosage reduction was required.
The incidence of grade 3 skin rash, noted in four (33%) patients. These rashes were described as violaceous and morbiliform, with associated pruritus and erythema in the face, trunk, and extremities. The median time to onset of the rash was 11 days (range, 10–27 days) after initiation of bortezomib therapy. The rashes resolved after treatment with intravenous dexamethasone and diphenhydramine. Three of the four patients required one dosage reduction of bortezomib because of the rash, and the fourth patient was removed from therapy because of disease progression.
proteasome activity
The level of proteasome activity inhibition after the first administration of bortezomib was determined in eight (67%) of the 12 patients (Figure 3). Additional proteasome inhibition data from subsequent treatment courses were available from two of those eight patients (numbers 1 and 5), for a total of 11 data sets. The mean percentage (± standard deviation) of inhibition of specific chymotryptic activity, SpA, was 53.10% ± 13.33% (Figure 3). Similarly, the mean percentage of inhibition using the ratio of chymotryptic to tryptic activity, ChT:T, was 57.6% ± 9.41%. There was no correlation between the levels of inhibition of proteasome activity and any adverse effects (e.g. hematological effects, skin rash).
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plasma levels of cytokine biomarkers
We sought to define additional serum and tissue biological surrogate endpoints of bortezomib activity. Plasma samples were obtained from six patients before and after bortezomib treatment and analyzed for the presence of interleukin (IL)- 1ß, IL-6, IL-8, IL-10, IL-12 p70 and tumor necrosis factor (TNF)-
. (Table 4). Plasma IL-6 levels measured after bortezomib treatment were significantly reduced from the levels before treatment (P < 0.04). None of the levels of the other cytokines tested were significantly affected by the therapy (Table 4).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Bortezomib is a potentially promising new anti-tumor agent that is a highly selective inhibitor of the 26S proteasome. In this phase II study, we evaluated the efficacy of bortezomib in patients with metastatic breast cancer. Although bortezomib was shown to inhibit proteasome activity and reduce the circulating levels of IL6, these biological effects were not associated with a meaningful clinical activity; no objective clinical responses were observed. Therefore, we do not recommend further investigations of bortezomib as a single agent in treating metastatic breast cancer.
To date, clinical experience with bortezomib has shown only limited activity against solid tumors when used as a single agent [12–14]. However, bortezomib may have significant anti-tumor activity when used in combination with other active conventional agents [18, 19], and numerous trials using bortezomib combination regimens are currently pending. With regard to breast cancer, the potential efficacy of bortezomib with taxanes and anthracyclines is of particular interest. In a recent phase I trial of bortezomib plus docetaxel in anthracycline-pretreated advanced breast cancer, six of nine patients achieved partial response; a phase II study is planned [15]. Another phase I trial is currently investigating bortezomib plus pegylated liposomal doxorubicin in refractory solid tumors, including several breast cancers [16].
In our study, pharmacodynamics data were available from eight of the 12 patients. The level of proteasome activity inhibition (SpA mean 53.1%, SD = 13.3%; range, 25.9%–74.6%; ChT:T mean 57.6%, SD = 9.41%; range, 41.1%–68.2%) was somewhat less than what has been previously reported (mean, 
65–70%) for a bortezomib dose of 1.5 mg/m2 [12, 13]. Others have shown a dose-dependent inhibition of proteasome activity [11, 13], and a possible correlation between the level of proteasome inhibition with both response and adverse effects has been proposed.
Pre- and post-therapy plasma cytokine levels were also available for six patients in our study. Previously, the presence of high levels of circulating IL-6 in breast cancer patients was significantly correlated with a shorter survival and associated with increased incidence of joint pain and flu-like symptoms in patients receiving paclitaxel chemotherapy [22, 23]. Furthermore, IL-6 was identified as an independent adverse prognostic variable for overall survival [17]. We demonstrated a statistically significant reduction in plasma IL-6 levels after the administration of bortezomib; however, because of the limited number of samples available for analysis, we were unable to ascertain correlations between plasma IL-6 levels and proteasome activity inhibition.
Bortezomib was generally well tolerated, and its toxicity profile was compatible with that reported in the literature [12–14]. An unexpected finding, however, was the relatively high incidence of skin rash. Rash was previously reported as being an infrequent and usually mild adverse effect [18, 19]. More recently, a grade 3 rash due to necrotizing vasculitis was reported in lymphoma patients [20], as well as a purpuric rash due to leukocytoclastic vasculitis in a myeloma patient [21].
In conclusion, although bortezomib was able to inhibit proteasome activity and reduce the circulating levels of IL-6, these biologic effects did not translate into a meaningful therapeutic benefit and we conclude that single-agent bortezomib does not appear to have clinically significant activity in metastatic breast cancer. These results can be partially explained by the observation that patients enrolled in this study had particularly aggressive metastatic disease with extremely poor prognosis and low probability of response to additional therapy [22, 23]. Therefore, we believe that an appropriate prognostic stratification of patients with metastatic disease using novel available technologies should support the further development of bortezomib either as a single agent, but most appropriately in combination regimens [24].
Received for publication November 7, 2005. Revision received November 24, 2005. Accepted for publication December 2, 2005.
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