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Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1052-1056 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.1053 Fulvestrant in Women With Advanced Breast Cancer After Progression on Prior Aromatase Inhibitor Therapy: North Central Cancer Treatment Group Trial N0032From the Mayo Clinic and Mayo Foundation, Rochester, MN; Carle Cancer Center Community Clinical Oncology Program (CCOP), Urbana; Illinois Oncology Research Association CCOP, Peoria, IL; Geisinger Clinic and Medical Center CCOP, Danville, PA; Scottsdale CCOP, Scottsdale, AZ; Duluth CCOP, Duluth, MN; Mayo Clinic Jacksonville, Jacksonville, FL; and Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada Address reprint requests to James N. Ingle, MD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: ingle.james{at}mayo.edu
PURPOSE: Fulvestrant is an antiestrogen that leads to estrogen receptor degradation and has demonstrated efficacy in breast cancer patients who have had disease recurrence or progression after tamoxifen. This study was designed to examine the efficacy and toxicity of fulvestrant in patients with disease progression on a third-generation aromatase inhibitor (AI). PATIENTS AND METHODS: A one-stage phase II trial was conducted in postmenopausal women with measurable disease by Response Evaluation Criteria in Solid Tumors criteria who experienced disease progression after treatment with a third-generation AI and, at most, one additional hormonal agent. Tumors must have been estrogen receptor and/or progesterone receptor positive. The primary end point was objective response rate, and secondary end points were time to disease progression, survival, duration of response, and toxicity. RESULTS: Eighty patients were enrolled, and three were ineligible. Characteristics of the 77 eligible patients included median age of 68 years, performance score of 0 or 1 in 91% of patients, visceral dominant disease in 88% of patients, two prior hormonal treatments in 73% of patients, and prior chemotherapy for metastatic disease in 32% of patients. Eleven patients (14.3%) achieved a partial response, and 16 patients (20.8%) had stable disease for at least 6 months, for a clinical benefit rate of 35%. Antitumor activity seemed to be higher in women with prior treatment with AI alone compared with women whose prior treatment also included tamoxifen. Median time to progression was 3 months, and median survival time was 20.2 months. Fulvestrant was well tolerated. CONCLUSION: Fulvestrant is a well-tolerated treatment and has efficacy against breast cancers that have progressed after therapy with a third-generation AI.
Hormonal therapy is the preferred treatment approach for most postmenopausal women with hormone receptor–positive advanced breast cancer. As their disease progresses, it is common practice to use multiple different hormonal agents in sequence in those patients who remain hormonal therapy candidates based on tempo, sites, and extent of disease and response to prior hormonal therapy. Third-generation aromatase inhibitors (AI) anastrozole, exemestane, and letrozole have become established as efficacious therapies in the advanced breast cancer setting in both patients whose disease has and has not progressed on tamoxifen.1 However, clinical trial data examining the potential benefits of administrating a hormonal agent after disease progression on an AI are limited.2 A phase II clinical trial in 105 postmenopausal women with metastatic breast cancer whose disease had progressed after treatment with a nonsteroidal AI (anastrozole, letrozole, or vorozole) revealed that exemestane, a steroidal aromatase inactivator, produced an objective response rate (complete response [CR] or partial response [PR]) of 4.8%, with an additional 15.6% of patients achieving stable disease for at least 24 weeks.3 There are few data on patients treated with a nonsteroidal AI after progression on exemestane, although one PR was observed in 10 patients so treated.4 A phase II clinical trial of diethylstilbestrol as a treatment for postmenopausal women with advanced breast cancer who had previously been exposed to multiple endocrine regimens (range, two to 10 regimens) revealed a 31% objective response rate (12% CR and 19% PR) in the 32 patients enrolled.5 All patients in this trial had received an AI, with 19 having received a third-generation AI (anastrozole and/or exemestane), five patients having received a second-generation AI (formestane), and eight patients having received the first-generation AI aminoglutethimide. Thus, the knowledge base relating to hormonal therapy after progression of breast cancer on AI therapy is limited. Fulvestrant, the long-acting formulation of ICI 182,780, is an antiestrogen that binds to and degrades the estrogen receptor and has estrogen antagonistic activity but no estrogen agonistic effect.6,7 Fulvestrant has been shown in two prospective, randomized, phase III, clinical trials to be at least as effective as anastrozole in postmenopausal women whose disease had progressed on prior hormonal therapy.8-10 The US Food and Drug Administration has approved fulvestrant for women whose disease has progressed after an antiestrogen. However, given the increasing role of AIs in both the advanced disease and adjuvant therapy settings,11 many of these women will also have experienced disease progression on a third-generation AI. This trial was undertaken to determine the efficacy of fulvestrant in women with advanced breast cancer who had experienced disease progression on a third-generation AI.
This trial enrolled postmenopausal women with histologically confirmed adenocarcinoma of the breast that had progressed after treatment with a third-generation AI (ie, anastrozole, exemestane, letrozole, or vorozole) and, at most, one other hormonal agent. Patients were required to fulfill the following eligibility requirements. Patients with metastatic disease must have had histologic or cytologic proof of metastasis, except in the case of multiple pulmonary nodules known to be new or unequivocal radiographic evidence of multiple bone metastases. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria12 was required. The breast cancer must have been estrogen receptor positive and/or progesterone receptor positive (defined as  10 fmol/mg cytosol protein when determined by a biochemical ligand-binding assay or positive by institutional standards when immunocytochemistry methodology was used). Evidence of hormonal sensitivity was required and was defined in the case of adjuvant hormonal therapy as at least 12 months of treatment before relapse; in the case of treatment in the advanced disease setting, it was defined as tumor response or stabilization for at least 12 months before progression. A postmenopausal status was required according to one of the following criteria: at least 12 months from the last menstrual period, 4 to 11 months since last menstrual period and follicle-stimulating hormone in postmenopausal range, prior castration, or age younger than 60 years and prior hysterectomy without oophorectomy and follicle-stimulating hormone in postmenopausal range.
Patients must have experienced disease progression after no more than one hormonal agent (eg, tamoxifen) in addition to the third-generation AI. Patients were considered to have had disease progression on tamoxifen if disease recurrence was identified 12 months or less from stopping of tamoxifen. For this trial, ovarian function suppression or ablation with oophorectomy, ovarian irradiation, or luteinizing hormone–releasing hormone analogs were not considered in determining prior hormonal therapies. Prior adjuvant chemotherapy, up to one chemotherapy regimen for metastatic disease, and prior trastuzumab were allowed. Bisphosphonate therapy was permitted, but bone lesions were only assessable for progression. Estrogen replacement or investigational drug therapy within 4 weeks of registration, luteinizing hormone–releasing hormone analog therapy within 3 months of registration, and warfarin therapy were not permitted. The following medical conditions made the patient ineligible: a bleeding diathesis, viral hepatitis B or C, AIDS, serologic evidence of HIV, unstable respiratory or cardiac disease, and other severe or uncontrolled systemic disease. Patients must have had an Eastern Cooperative Oncology Group performance score of 0, 1, or 2 and a life expectancy of at least 3 months. Patients were not eligible if they had the following known metastasis: brain, leptomeningeal, symptomatic pulmonary lymphangitic, or hepatic estimated to involve more than one third of the liver. The following laboratory values, obtained within 14 days of registration, were required: leukocyte count Studies obtained before entry onto the protocol included a medical history; physical examination with assessment of tumor lesion(s), hemoglobin, leukocyte count, and platelet count; serum calcium, alkaline phosphatase, AST, total bilirubin, and creatinine measurement; prothrombin time; and chest radiograph. This trial was performed after approval by local institutional review boards in accordance with assurances filed with and approved by the US Department of Health and Human Services. Written informed consent was provided by each patient before entry onto the study. After registration, patients were treated with fulvestrant (supplied as Faslodex; AstraZeneca Pharmaceuticals, Wilmington, DE) 250 mg in 5 mL of solution from a prefilled syringe as a single intramuscular injection over at least 2 minutes into the gluteus maximus muscle. The intervals to re-treatment were 28 ± 3 days. There were no dose modifications for adverse events. After initiation of therapy, patients were assessed at 1 month, at 3 months, and every 3 months thereafter using the RECIST criteria.12 Treatment was continued until the identification of progression of the breast cancer. In accordance with RECIST criteria, CR and PR must have been confirmed by repeat assessments at least 4 weeks after criteria were first met. A one-stage phase II clinical trial was conducted to assess the tumor response rate and toxicity profile of fulvestrant as a treatment for women whose breast cancer had progressed during treatment with an AI. The primary end point of this study was tumor response rate. The tumor response rate was defined as the total number of eligible patients who achieved a CR or PR according to the RECIST criteria divided by the total number of eligible patients enrolled onto the study. A clinical benefit rate was determined by the total number of eligible patients who achieved a CR or PR plus those who had stable disease for at least 6 months.
A one-stage phase II design was chosen for this study so that, at a P = .06 significance level, there would be a 87% chance of rejecting that the tumor response rate is at most 10% in this patient population when the true tumor response rate is at least 20% in this patient population. A total of 89 eligible patients were to be enrolled. If 14 or more of the 89 eligible patients enrolled achieved a PR or CR by the RECIST criteria without excessive toxicity, consideration would be given to recommend this treatment for further testing in this patient population. Because of a slow accrual rate, the trial was closed to accrual after the enrollment of 77 eligible patients. With a sample size of 77 eligible patients, a one sided, The true response rate was estimated by proportion of eligible patients who achieved a CR or PR. A 90% CI for the true response rate was constructed using the properties of the binomial distribution. Time to progression was defined as the time from registration to disease progression. Patients who died without documentation of progression were considered to have progressed on the date of their death. Survival time was defined as the time from registration to death. Time to event distributions were estimated using the Kaplan-Meier method.
Eighty women were enrolled onto this clinical trial from June 2002 to May 2004. Three patients were found to be ineligible because of estrogen receptor–negative and progesterone receptor–negative recurrent disease (two patients) and more than one chemotherapy regimen for metastatic disease (one patient). Characteristics of the 77 eligible patients at the time of registration are listed in Table 1. Five patients had undergone oophorectomy from 1 to 42 years before the diagnosis of breast cancer.
The median number of cycles administered was two (range, one to 10+ cycles). All but two patients have discontinued treatment. The reasons include progression of disease (65 patients), refusal (three patients), cardiac arrest (one patient), physician discretion (one patient), clinical deterioration (one patient), death as a result of pneumonia (one patient), death as a result of clinical deterioration (one patient), and loss of the ability to supply Canadian institution with drug (two patients, each after 13.5 months on study).
Response Among the 21 patients who had not received prior tamoxifen, six patients (28.6%) achieved a PR, and five patients (23.8%) had tumors that remained stable for at least 6 months. Among the 56 patients who had received prior tamoxifen, five patients (8.9%) achieved a PR, and 11 patients (19.6%) had tumors that remained stable for at least 6 months. Thus, the clinical benefit rate was 52.4% (90% CI, 32.8% to 71.4%) among patients who had not received prior tamoxifen and 28.6% (90% CI, 18.8% to 40.1%) among patients who had received prior tamoxifen. These data are listed in Table 2.
Survival and Disease Progression At last contact, six patients were alive without progression, 18 patients were alive with disease progression, one patient died of pneumonia, and 52 patients died after disease progression (Fig 1). The median follow-up time for the 24 patients still alive is 1.5 years (range, 3 months to 3.7 years).
The median survival time was 20.2 months, and the 1-year survival rate was estimated to be 70.9% (95% CI, 61.3% to 82.0%). The median time to progression was estimated to be 3 months, and the 1-year disease progression–free rate was estimated to be 18.5% (95% CI, 11.5% to 29.7%).
Toxicity
Fulvestrant has antitumor activity in postmenopausal women with metastatic breast cancer that has progressed on prior therapy with a third-generation AI, with an observed response rate of 14.3% (90% CI, 8.2% to 22.5%). More than one third of women obtained clinical benefit by virtue of achieving a PR (14.3%) or having stable disease for at least 6 months (20.8%). This benefit was achieved with only three patients (4%) experiencing a grade 3 adverse event considered at least likely to be related to treatment.
Perey et al13 evaluated 67 women entered onto a phase II trial who had received tamoxifen and an AI with which they had achieved a response. Prior chemotherapy had been administered to 46% of the patients, with 10% having received the chemotherapy in the advanced disease setting. They observed one patient (1%) with a PR and 18 patients (27%) with stable disease for Steger et al14 reported on 68 patients who received fulvestrant in a compassionate use program after progression on at least two hormonal therapies. All patients had received prior tamoxifen and either anastrozole or exemestane. Twenty-five patients (38%) received fulvestrant as second-line palliative therapy, 31 patients (46%) received fulvestrant as third-line therapy, and 12 patients (18%) received fulvestrant as fourth-line therapy. Sixty patients were assessable for response, five patients (8%) achieved a PR, and 31 women (52%) had stable disease for at least 6 months, for a clinical benefit rate of 60%. Fulvestrant was well tolerated. A single-center experience was reported by Franco et al15 that involved 42 women who had been heavily pretreated with hormonal therapy. All patients had received a prior AI, 26 patients (62%) had received prior tamoxifen or toremifene, and half of the patients had received four or more hormonal agents. The mean number of chemotherapy regimens for advanced disease was 2.7, and 74% of patients had received at least one chemotherapy regimen. No objective responses were seen, but eight patients (19%) had stable disease for at least 24 weeks. The drug was considered well tolerated, although there were three withdrawals as a result of adverse events that were said to involve bone pain. The published experience with fulvestrant indicates that it has antitumor activity in patients with advanced breast cancer who have received prior AI therapy. We observed that the benefit seemed to be higher in women who had received only a prior AI (PR rate, 29%; clinical benefit rate, 52%) compared with patients who had received both an AI and tamoxifen (PR rate, 9%; clinical benefit rate, 29%); this observation must be interpreted with caution because the sample sizes were small (21 and 56 patients, respectively). It may be that the higher efficacy in the patients with only prior AI therapy is simply related to one instance of disease progression rather than two and less hormonal therapy before the fulvestrant. Indirect cross-study comparisons must be done with caution, but the level of benefit with fulvestrant seems to be at least as good as that reported for exemestane after nonsteroidal AIs.3 It is clear that additional clinical trials need to be performed in the so-called salvage setting to determine the relative efficacy of different agents.2 Although fulvestrant has demonstrated clear evidence of efficacy, the question can be raised as to whether it is being administered in the optimal dose and schedule given that it takes 3 to 6 months to reach steady state.16 The issue of dose and schedule is currently under investigation in several clinical trials. In addition, fulvestrant is currently being evaluated in a variety of clinical trials as recently reviewed.17 Further study is needed to determine the optimal sequence of hormonal therapy after an AI because this class of drugs has become established in the adjuvant and advanced breast cancer settings. However, fulvestrant is an agent that has demonstrated clear activity and good tolerability in women who have experienced disease progression on third-generation AIs. It provides a reasonable treatment option for such women who clinically remain candidates for endocrine therapy. The observation that there may be a higher level of benefit with fulvestrant after AI therapy alone than when preceded by both an AI and tamoxifen needs confirmation.
The following institutions also participated in this study: Siouxland Hematology-Oncology Associates, Sioux City, IA (John C. Michalak, MD); Wichita Community Clinical Oncology Program Community Clinical Oncology Program (CCOP), Wichita, KS (Shaker R. Dakhil, MD); Missouri Valley Cancer Consortium, Omaha, NE (James A. Mailliard, MD); Michigan Cancer Consortium, Ann Arbor, MI (Philip J. Stella, MD); Medcenter One Health Systems, Bismarck, ND (Edward J. Wos, DO); Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA (Martin Wiesenfeld, MD); Meritcare Hospital CCOP, Fargo, ND (Preston D. Steen, MD); Altru Health Systems, Grand Forks, ND (Tudor Dentchev, MD); Metro-Minnesota Community Clinical Oncology Program, St Louis Park, MN (Patrick J. Flynn, MD); and Upstate Carolina CCOP, Spartanburg, SC (James D. Bearden III, MD).
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported in part by Public Health Service Grant Nos. CA-25224, CA-37404, CA-35195, CA-63848, CA-52352, CA-35269, CA-37417, CA-35448, CA-35267, CA-63849, CA-35113, CA-60276, CA-35119, and CA-35431 from the National Institutes of Health. Presented in part at the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Ingle JN, Suman VJ: Aromatase inhibitors for therapy of advanced breast cancer. J Steroid Biochem Molec Biol 95:113-119, 2005[CrossRef][Medline] 2. Ingle JN: Sequencing of endocrine therapy in postmenopausal women with advanced breast cancer. Clin Cancer Res 10:362s-367s, 2004 (suppl)[Medline] 3. Lonning PE, Bajetta E, Murray R, et al: Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors. J Clin Oncol 18:2234-2244, 2000 4. Bertelli G, Garrone O, Merlano M: Sequential use of aromatase inactivators and inhibitors in advanced breast cancer. Proc Am Soc Clin Oncol 21:60a, 2002 (abstr 238) 5. Lonning PE, Taylor PD, Anker G, et al: High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat 67:111-116, 2001[CrossRef][Medline] 6. Wakeling AE, Dukes M, Bowler J: A potent pure antiestrogen with clinical potential. Cancer Res 51:3867-3873, 1991 7. Wakeling AE: Similarities and distinctions in the mode of action of different classes of antiestrogens. Endocr Relat Cancer 7:17-28, 2000[CrossRef][Medline] 8. Osborne CK, Pippen J, Jones SE, et al: Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: Results of a North American trial. J Clin Oncol 20:3386-3395, 2002 9. Howell A, Robertson JFR, Quaresma Albano J, et al: Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20:3396-3403, 2002 10. Robertson JFR, Osborne CK, Howell A, et al: Fulvestrant versus anastrozole for the treatment of advanced breast cancer in postmenopausal women: A prospective combined analysis of two multicenter trials. Cancer 98:229-238, 2003[CrossRef][Medline] 11. Ingle JN: Endocrine therapy trials of aromatase inhibitors for breast cancer in the adjuvant and prevention settings. Clin Cancer Res 11:900S-905S, 2005 (suppl)[Medline] 12. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 13. Perey L, Paridaens R, Nole F, et al: Fulvestrant (Faslodex) as hormonal treatment in postmenopausal patients with advanced breast cancer progressing after treatment with tamoxifen and aromatase inhibitors: Update of a phase II SAKK trial. Breast Cancer Res Treat 88:S236, 2004 (suppl) 14. Steger GG, Bartsch R, Wenzel C, et al: Fulvestrant in metastatic breast cancer. Breast Cancer Res Treat 82:S104, 2003 (suppl 1) 15. Franco S, Perez A, Tan-Chiu E, et al: Response to fulvestrant in heavily pretreated postmenopausal women: A single-center experience. Breast Cancer Res Treat 33:103-108, 2004 16. Robertson JFR, Erikstein B, Osborne CK, et al: Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer. Clin Pharmacokinet 43:529-538, 2004[CrossRef][Medline] 17. Gradischar WJ, Sahmoud T: Current and future perspectives on fulvestrant. Clin Breast Cancer 6:s23-s29, 2005 (suppl 1)[Medline] Submitted September 1, 2005; accepted December 28, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10% above the upper limit of institutional normal (ULIN), serum total bilirubin 
= .08, one-sample test of proportions would have approximately a power of 87% of rejecting that the tumor response rate is at most 10% in this patient population when the true tumor response rate is at least 20% in this patient population. That is, if 12 or more of the 77 eligible patients enrolled achieved a PR or CR by the RECIST criteria without excessive toxicity, consideration would be given to recommend this treatment for further testing in this patient population. 
