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John F R Robertson

Publications and source records attributed to John F R Robertson.

At least 19 recordsLinked to original sources
PubMed2006

Fulvestrant: pharmacologic profile versus existing endocrine agents for the treatment of breast cancer.

OBJECTIVE: To compare the pharmacologic profile of fulvestrant with that of tamoxifen and the aromatase inhibitors with respect to the choice of treatment for advanced breast cancer (ABC). DATA SOURCES: Principal literature and review articles were obtained from MEDLINE (1991-March 2006). Key search terms included fulvestrant, tamoxifen, aromatase inhibitors, pharmacology, and breast cancer. Further data sources were identified from the bibliographies of selected articles. STUDY SELECTION AND DATA EXTRACTION: English-language preclinical and clinical research and review articles reporting pharmacologic and safety data for fulvestrant, tamoxifen, and the aromatase inhibitors were evaluated to identify relevant information. Randomized clinical trial data were preferred over preclinical or Phase I and II trial data. DATA SYNTHESIS: A total of 52 clinical papers (including 10 reviews) and 17 clinical abstracts were evaluated reporting results from controlled Phase I-III studies and pilot studies. Eleven preclinical papers (including 2 reviews) and 6 preclinical abstracts were also included. Fulvestrant has little effect on sex hormone endocrinology, bone metabolism, and lipid biochemistry and appears unlikely to be the subject or cause of CYP3A4-mediated drug interactions. Tamoxifen has a protective effect on bone (due to its partial estrogen agonist activity) and reduces plasma low-density lipoprotein cholesterol but increases triglyceride levels. The aromatase inhibitors have variable effects on lipid profiles and sex hormone endocrinology but have detrimental effects on bone due to inhibition of estrogen synthesis. Drug interactions have been noted between tamoxifen and anticoagulants and tamoxifen and aromatase inhibitors, which may be due to CYP-mediated mechanisms. CONCLUSIONS: Fulvestrant appears to have little effect on sex hormone endocrinology, bone metabolism, and lipid biochemistry and is unlikely to be subject to or the cause of CYP3A4-mediated drug-drug interactions. As such, fulvestrant represents a valuable new endocrine therapy for the treatment of ABC and broadens the options available to clinicians in the treatment of this disease.

Antineoplastic Agents, Hormonal↗
PubMed2006

Efficacy and tolerability of high dose "ethinylestradiol" in post-menopausal advanced breast cancer patients heavily pre-treated with endocrine agents.

BACKGROUND: High dose estrogens (HDEs) were frequently used as endocrine agents prior to the introduction of tamoxifen which carries fewer side effects. Due to the development of resistance to available endocrine agents in almost all women with metastatic breast cancer, interest has renewed in the use of HDEs as yet another endocrine option that may have activity. We report our experience with one of the HDEs ("ethinylestradiol" 1 mg daily) in advanced breast cancer (locally advanced and metastatic) in post-menopausal women who had progressed on multiple endocrine agents. PATIENTS AND METHODS: According to a database of advanced breast cancer patients seen in our Unit since 1998, those who had complete set of information and fulfilled the following criteria were studied: (1) patients in whom further endocrine therapy was deemed appropriate i.e., patients who have had clinical benefit with previous endocrine agents or were not fit or unwilling to receive chemotherapy in the presence of potentially life-threatening visceral metastases; (2) disease was assessable by UICC criteria; (3) were treated with "ethinylestradiol" until they were withdrawn from treatment due to adverse events or disease progression. RESULTS: Twelve patients with a median age of 75.1 years (49.1-85 years) were identified. Majority (N = 8) had bony disease. They had ethinylestradiol as 3rd to 7th line endocrine therapy. One patient (8%) came off treatment early due to hepato-renal syndrome. Clinical benefit (objective response or durable stable disease for > or = 6 months) was seen in 4 patients (33.3%) with a median duration of response of 10+ (7-36) months. The time to treatment failure was 4 (0.5-36) months. CONCLUSION: Yet unreported, high dose "ethinylestradiol" is another viable therapeutic strategy in heavily pre-treated patients when further endocrine therapy is deemed appropriate. Although it tends to carry more side effects, they may not be comparable to those of other HDEs (such as diethylstilbestrol) or chemotherapy.

Journal Article↗
PubMed2006

"Resurrection of clinical efficacy" after resistance to endocrine therapy in metastatic breast cancer.

BACKGROUND: In a significant proportion of metastatic breast cancer (MBC) patients whose tumour has progressed within 6 months of endocrine therapy (de novo resistance), it is generally believed that the chance of achieving clinical benefit (CB) with further endocrine therapy is minimal. METHODS: Data was retrieved from a prospectively updated database of metastatic breast cancer. Relevant data was exported to SPSS software for statistical analysis. RESULTS: In oestrogen receptor (ER) positive MBC patients with assessable disease, CB was achieved in 159 (71.3%) (1st line) patients. When these patients were put on further endocrine therapy, the CB rates were 63.2% (on 2nd line), 46.1% (on 3rd line) and 20% (on 4th line) with a median duration of response (DOR) in those with CB of 22, 12, 11 and 15 months respectively. The remaining 64 (28.7%) patients had de novo resistance on 1st line endocrine therapy. Seventeen of these patients were treated with further endocrine therapy. The CB rates were 29.4% (on 2nd line) and 22.2% (on 3rd line) with a median DOR in those with CB of 22.7 months and 14 months respectively. CONCLUSION: The chance of further endocrine response continues to decrease with each line of therapy, yet CB is still seen with reasonable duration even with a 4th line agent. In addition, further endocrine response, with long duration, can be seen in a significant proportion of patients who have developed de novo resistance to 1st line endocrine therapy. The use of further endocrine therapy should not be excluded under these circumstances.

Journal Article↗
PubMed2006

The reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast.

AIM: To assess the reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast. Previous studies have mostly been small, with a range of agreement from 62% to 100%. METHODS: Retrospective audit of 338 tumours surgically excised within 60 days of core biopsy, that had had oestrogen receptor assessed on both the core biopsy and tumour specimens. Surgical specimens were incised when fresh to ensure good fixation. External controls including a weakly positive tumour were included in each immunohistochemistry run. RESULTS: Oestrogen receptor expression was bimodal, with H score in both specimens of either 0 or >50 in 96% of tumours. Using H score cut-off of 10 for positivity, there was an agreement between core and excision in 334 of 338 tumours (98.8%). All discrepancies were between weakly positive and negative tumours. Intratumoral heterogeneity could explain the one tumour that was negative on core and positive on excision. H score tended to be slightly higher on core than excision (means 146 and 136). Better fixation on the core is the most likely explanation for this and for the three tumours that were positive on core and negative on excision. Repeat staining on tumours with discrepant results gave similar results in all except one case. An internal control was present in 97% of excisions and 55% of cores of oestrogen receptor-negative tumours; the internal control stained positively in all except two sections. CONCLUSION: Oestrogen receptor can be assessed reliably on needle core biopsies of invasive carcinomas of the breast.

Adenocarcinoma↗
PubMed2006

Use of autoantibodies in breast cancer screening and diagnosis.

Breast cancer is the most common cancer among women and accounts for 6% of all cancer deaths. Current screening modalities for breast cancer diagnosis include mammography, digital mammography and magnetic resonance imaging; however, there is still an urgent need to develop an alternative modality of screening for earlier diagnosis. Autoantibodies to tumor-associated autoantigens can be elicited in breast cancer patients. Tumor-associated antigens vary between cancers and can be the result of a number of different events, including mutation, overexpression or altered expression patterns. The inherent amplification of signals provided by the host's own immune system to low levels of tumor-associated antigens in early disease provides a potential route to the early diagnosis of cancer. In addition, autoantibody responses in breast cancer have been correlated with patient survival and their response to treatment.

Autoantibodies↗
PubMed2005

High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses.

Recent studies on gene molecular profiling using cDNA microarray in a relatively small series of breast cancer have identified biologically distinct groups with apparent clinical and prognostic relevance. The validation of such new taxonomies should be confirmed on larger series of cases prior to acceptance in clinical practice. The development of tissue microarray (TMA) technology provides methodology for high-throughput concomitant analyses of multiple proteins on large numbers of archival tumour samples. In our study, we have used immunohistochemistry techniques applied to TMA preparations of 1,076 cases of invasive breast cancer to study the combined protein expression profiles of a large panel of well-characterized commercially available biomarkers related to epithelial cell lineage, differentiation, hormone and growth factor receptors and gene products known to be altered in some forms of breast cancer. Using hierarchical clustering methodology, 5 groups with distinct patterns of protein expression were identified. A sixth group of only 4 cases was also identified but deemed too small for further detailed assessment. Further analysis of these clusters was performed using multiple layer perceptron (MLP)-artificial neural network (ANN) with a back propagation algorithm to identify key biomarkers driving the membership of each group. We have identified 2 large groups by their expression of luminal epithelial cell phenotypic characteristics, hormone receptors positivity, absence of basal epithelial phenotype characteristics and lack of c-erbB-2 protein overexpression. Two additional groups were characterized by high c-erbB-2 positivity and negative or weak hormone receptors expression but showed differences in MUC1 and E-cadherin expression. The final group was characterized by strong basal epithelial characteristics, p53 positivity, absent hormone receptors and weak to low luminal epithelial cytokeratin expression. In addition, we have identified significant differences between clusters identified in this series with respect to established prognostic factors including tumour grade, size and histologic tumour type as well as differences in patient outcomes. The different protein expression profiles identified in our study confirm the biologic heterogeneity of breast cancer and demonstrate the clinical relevance of classification in this manner. These observations could form the basis of revision of existing traditional classification systems for breast cancer.

Breast Neoplasms↗
PubMed2005

Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials.

BACKGROUND: Fulvestrant is an estrogen receptor antagonist with no agonist effects. In the second-line treatment of advanced breast carcinoma, fulvestrant was shown previously to be as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to disease progression and objective response rates. The authors reported the overall survival results from these studies. METHODS: A prospectively planned, combined, overall survival analysis was performed, including data from two Phase III trials that compared the efficacy and tolerability of fulvestrant (250 mg monthly; n = 428) with anastrozole (1 mg daily; n = 423) in the treatment of postmenopausal women with advanced breast carcinoma who had disease progression after receipt of previous endocrine treatment. RESULTS: At an extended median follow-up of 27.0 months (range, 0-66.9 months), 319 (74.5%) patients in the fulvestrant group and 322 (76.1%) patients in the anastrozole group had died. Prolonged survival was observed with both drugs, with 10-20% of patients still alive > 5 years after randomization. The median overall survival was similar between treatments, being 27.4 months and 27.7 months in fulvestrant and anastrozole-treated patients, respectively (hazards ratio, 0.98; 95% confidence interval, 0.84-1.15; P = 0.809). Fulvestrant continued to be well tolerated, and was associated with a significantly lower incidence of joint disorders compared with anastrozole (P = 0.0234). CONCLUSIONS: The current analysis showed that fulvestrant was similar to anastrozole with respect to overall survival in the second-line treatment of postmenopausal women with advanced breast carcinoma.

Anastrozole↗
PubMed2005

Selective use of post-mastectomy flap irradiation in high-risk breast cancer patients.

The incidence of local recurrence after mastectomy can be reduced by chest wall radiotherapy. However, only a minority of patients are at substantial risk. No UK national guidelines exist for the use of mastectomy flap radiotherapy. This study evaluated a protocol, whereby only high-risk patients were treated with post-mastectomy flap radiotherapy; identified histologically by grade, vascular invasion and nodal status. All women treated by simple mastectomy for invasive breast cancer at the Nottingham Breast Unit from January 1993 to December 1995 were studied (n=292). Postoperative flap radiotherapy was given to 147 high-risk women (50.3%). Median follow-up was 76 months. Overall, 12 women (4.1%) developed a chest wall recurrence; six were single spot recurrences and the remaining six were either multiple spot (n=3) or field change (field change dermal invasion, n=3). The chest wall recurrence rate was 2.7% in those treated with radiotherapy. A low rate of local recurrence has been achieved with selective use of mastectomy flap radiotherapy.

Adult↗
PubMed2005

Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer.

Mucins are a large family of glycoproteins expressed by many epithelial cells and their malignant counterparts. Much interest has been focused on expression of its members in breast cancer because of their potential role as prognostic indicators and their involvement in cancer therapy. We have examined 1447 cases of invasive breast carcinoma with a long-term follow-up, using tissue microarray (TMA) technology and immunohistochemistry to evaluate the expression profiles of several mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and to assess their prognostic value. We detected MUC1 expression in 91% of tumours. MUC1 overexpression was associated with a lower grade, smaller tumour size, a higher oestrogen receptor (ER)-positive phenotype and absence of both regional recurrence and distance metastasis. The subcellular localization but not the level of expression had a prognostic value in predicting outcome. The aberrant cytoplasmic and membranous localization of MUC1 was associated with poor outcome compared with apical localization, which is the normal physiological site of expression. MUC2 expression was noticed in only 8.3% of all cases and was restricted to the cytoplasm of the tumour cells. An inverse trend was identified between MUC2 expression and lymph node stage and vascular invasion status. On excluding cases of mucinous carcinoma from the analysis, the inverse association with vascular invasion was still defined and in addition an inverse association with ER status emerged. MUC3 expression was detected in 91% of cases and its expression was associated with increased local recurrence, and lymph node stage. The membranous expression of MUC3 was found to be a potentially poor prognostic feature, with higher grade and poorer Nottingham Prognostic Index (NPI), and negative ER expression. MUC4, MUC5AC and MUC6 were expressed in 95, 37 and 20% of cases, respectively. Apart from an association between MUC4 expression and tumour grade and between MUC6 and ER-negative tumours, no other associations with any clinicopathological variables were found. Apart from the higher expression of MUC2 and MUC6 in mucinous carcinomas, no association was found between the expression of different mucins and tumour type. No association between the level of expression of any of the studied mucins and patient outcomes has been identified. In conclusion, most breast carcinomas express MUC1, MUC3 and MUC4. Among the various mucins expressed in breast cancer, MUC1 and MUC3 are potential prognostic indicators, MUC1 having the strongest relationship with patient outcome.

Adolescent↗
PubMed2004

Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial.

PURPOSE: To evaluate the efficacy and tolerability of fulvestrant (Faslodex; AstraZeneca Pharmaceuticals LP, Wilmington, DE), a new estrogen receptor (ER) antagonist that downregulates ER and has no agonist effects, versus tamoxifen, an antiestrogen with agonist and antagonist effects, for the treatment of advanced breast cancer in postmenopausal women. PATIENTS AND METHODS: In this multicenter, double-blind, randomized trial, patients with metastatic/locally advanced breast cancer previously untreated for advanced disease were randomly assigned to receive either fulvestrant (250 mg, via intramuscular injection, once monthly; n = 313) or tamoxifen (20 mg, orally, once daily; n = 274). Patients' tumors were positive for ER (ER+) and/or progesterone receptor (PgR+), or had an unknown receptor status. RESULTS: At a median follow-up of 14.5 months, there was no significant difference between fulvestrant and tamoxifen for the primary end point of time to progression (TTP; median TTP, 6.8 months and 8.3 months, respectively; hazard ratio, 1.18; 95% CI, 0.98 to 1.44; P =.088). In a prospectively planned subset analysis of patients with known ER+ and/or PgR+ tumors ( approximately 78%), median TTP was 8.2 months for fulvestrant and 8.3 months for tamoxifen (hazard ratio, 1.10; 95% CI, 0.89 to 1.36; P =.39). The objective response rate for the overall population was 31.6% with fulvestrant and 33.9% with tamoxifen, and 33.2% and 31.1%, respectively, in the known hormone receptor-positive subgroup. Both treatments were well tolerated. CONCLUSION: In the overall population, between-group differences in efficacy end points favored tamoxifen, and statistical noninferiority of fulvestrant could not be demonstrated. However, in patients with hormone receptor-positive tumors, fulvestrant had similar efficacy to tamoxifen and was well tolerated.

Administration, Oral↗
PubMed2004

Expression of luminal and basal cytokeratins in human breast carcinoma.

We have examined basal and luminal cell cytokeratin expression in 1944 cases of invasive breast carcinoma, using tissue microarray (TMA) technology, to determine the frequency of expression of each cytokeratin subtype, their relationships and prognostic relevance, if any. Expression was determined by immunocytochemistry staining using antibodies to the luminal cytokeratins (CKs) 7/8, 18 and 19 and the basal markers CK 5/6 and CK 14. Additionally, assessment of alpha-smooth muscle actin (SMA) and oestrogen receptor status (ER) was performed. The vast majority of the cases showed positivity for CK 7/8, 18 and 19 indicating a differentiated glandular phenotype, a finding associated with good prognosis, ER positivity and older patient age. In contrast, basal marker expression was significantly related to poor prognosis, ER negativity and younger patient age. Multivariate analysis showed that CK 5/6 was an independent indicator for relapse free interval. We were able to subgroup the cases into four distinct phenotype categories (pure luminal, mixed luminal/basal, pure basal and null), which had significant differences in relation to the biological features and the clinical course of the disease. Tumours classified as expressing a basal phenotype (the combined luminal plus basal and the pure basal) were in a poor prognostic subgroup, typically ER negative in most cases. These findings provide further evidence that breast cancer has distinct differentiation subclasses that have both biological and clinical relevance.

Actins↗
PubMed2004

Selective oestrogen receptor modulators/new antioestrogens: a clinical perspective.

Following tamoxifen, the first selective oestrogen receptor modulator (SERM), a number of other antioestrogens have been developed. The first-generation SERMs exhibit cross-resistance with tamoxifen and have agonist effects on the uterus. Toremifene has equal efficacy to tamoxifen and may be useful as a tamoxifen alternative. Efficacy results for droloxifene and idoxifene were disappointing and their clinical development ceased. Response rates for second-generation SERMs such as raloxifene and arzoxifene are also not high, although raloxifene shows promise in the chemoprevention of breast cancer. Paradoxically, high-dose oestrogens are proving to be effective breast cancer treatment with similar responses to tamoxifen in postmenopausal women with advanced disease, although these drugs are not well tolerated. Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist effects, which binds, blocks and degrades the ER. Fulvestrant produces high response rates compared with the SERMs, is not cross-resistant with SERMs or aromatase inhibitors (AIs) and is equally as effective as the AI anastrozole in the treatment of postmenopausal women with advanced breast cancer who have progressed after prior antioestrogen therapy. Pure antioestrogens such as the ER antagonist fulvestrant provide opportunities for therapeutic sequencing with tamoxifen and AIs and offer exciting possibilities for the future treatment of breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed2004

Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer.

OBJECTIVE: To characterise the pharmacokinetics of a long-acting formulation of fulvestrant following intramuscular administration of single and multiple doses. STUDY DESIGN: Pharmacokinetic investigations of single and multiple doses of fulvestrant were conducted within two global phase III efficacy studies that compared intramuscular fulvestrant with oral anastrozole in postmenopausal women with hormone-sensitive advanced breast cancer (study 0020, conducted in Europe, Australia and South Africa, and study 0021, conducted in North America). METHODS: Patients received once-monthly intramuscular injections of fulvestrant 250 mg (1 x 5 mL for < or =21 months in study 0020; 2 x 2.5 mL for < or =30 months in study 0021). Serial blood samples were collected for the first 28 days after the initial dose and immediately prior to all subsequent monthly doses. Plasma fulvestrant concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. PATIENTS: Twenty-six (study 0020) and 193 (study 0021) postmenopausal women, comprising the pharmacokinetic subgroups of the phase III efficacy trials, were studied. Patients had shown disease progression or recurrence following previous hormonal therapy for advanced disease or had relapsed after adjuvant endocrine therapy with a nonsteroidal antiestrogen. OUTCOME MEASURES AND RESULTS: For single-dose fulvestrant 250 mg, area under the concentration-time curve from time zero to 28 days (AUC(28)), maximum observed plasma concentration (C(max)), minimum observed plasma concentration at 28 days (C(min)) and time to maximum plasma concentration (t(max)) were determined. For multiple-dose fulvestrant 250 mg once monthly, steady-state trough concentrations (C(trough)) were determined. Plasma fulvestrant concentrations reached a peak at a median of 7 days (range 2-8 days) postdose, and declined biexponentially with a slower phase commencing approximately 2-3 weeks postdose. Intersubject variability in C(max) and AUC(28) was approximately 6-fold and 4-fold, respectively. Mean parameters for single-dose fulvestrant were: AUC(28), 148 microg. day/L; C(max), 8.2 microg/L; C(min), 2.6 microg/L; t(max), 7.0 days. Geometric mean C(trough) increased from 2.57 to 6.15 microg/L (study 0020) and from 2.38 to 6.52 microg/L (study 0021) over the first 6 months, reaching steady-state concentrations of approximately 6-7 microg/L (study 0020) or 9 microg/L (study 0021). Preliminary pharmacokinetic analysis, using a naive pooled data approach, suggests that observed single- and multiple-dose plasma profiles can be adequately described with a two-compartment kinetic model. Model-generated steady-state AUC(28) values were approximately 300 microg. day/L. CONCLUSIONS: The intramuscular formulation of fulvestrant displays predictable kinetics and approximately 2-fold accumulation on administration once monthly. At the proposed therapeutic dosage (250 mg once monthly), plasma fulvestrant concentrations are maintained within a narrow range throughout the administration interval, thus ensuring stable systemic drug exposure during long-term treatment.

Adult↗
PubMed2003

Equivalent single-dose pharmacokinetics of two different dosing methods of prolonged-release fulvestrant ('Faslodex') in postmenopausal women with advanced breast cancer.

PURPOSE: To compare the pharmacokinetics of two different dosing methods of fulvestrant ('Faslodex'), an estrogen receptor antagonist with no known agonist activity, for the treatment of advanced breast cancer. METHODS: Postmenopausal women with advanced breast cancer were randomly assigned to receive a single 5-ml intramuscular injection of 250 mg fulvestrant, or two 2.5-ml intramuscular injections with a total of 250 mg fulvestrant. Blood samples were taken for pharmacokinetic analysis up to 28 days after injection. RESULTS: Plasma concentrations of fulvestrant were measurable up to 28 days after both dosing methods. The concentration-time profiles were relatively shallow, spanning an approximate threefold range from 3 h after dosing to Cmin measured on day 28. Peak plasma concentrations (Cmax) of fulvestrant occurred between 1 and 11 days after dosing, with mean Cmax values of 6.0 and 6.2 ng/ml following one 5-ml injection and two 2.5-ml injections, respectively. The plasma concentration-time profiles were very similar in terms of duration and concentration, and overall exposure to fulvestrant was similar in both dosing groups (the ratio of the AUC(0-28) of the single-injection group to that of the double-injection group was 1.01; 95% confidence interval 0.68-1.51). CONCLUSION: This study found no evidence of any pharmacokinetic difference between one 5-ml injection and two 2.5-ml injections. The two methods can be used interchangeably, depending on which is more convenient in any particular clinical setting.

Aged↗
PubMed2003

Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials.

BACKGROUND: Fulvestrant (ICI 182,780) is a new type of estrogen receptor (ER) antagonist that down-regulates the ER and has no known agonist effects. The authors report the prospectively planned combined analysis of data from 2 Phase III trials comparing fulvestrant 250 mg monthly (n=428) and anastrozole 1 mg daily (n=423) in postmenopausal women with advanced breast carcinoma (ABC) who previously had progressed after receiving endocrine treatment. METHODS: The primary endpoint was time to progression (TTP). Secondary endpoints included objective response (OR), duration of response (DOR), and tolerability. The trials were designed to demonstrate superiority of fulvestrant over anastrozole. Noninferiority of fulvestrant versus anastrozole was determined using a retrospectively applied statistical test. RESULTS: At a median follow-up of 15.1 months, approximately 83% of patients in each treatment arm had progressed. The median TTP was 5.5 months in the fulvestrant group and 4.1 months in the anastrozole group, and the OR rates were 19.2% and 16.5% for fulvestrant and anastrozole, respectively (although the difference between treatments was not statistically significant). In patients who responded, further follow-up (median, 22.1 months) was performed to obtain more complete information on DOR; the median DOR (from randomization to disease progression) in patients who responded to treatment was 16.7 months in the fulvestrant group and 13.7 months in the anastrozole group. In a statistical analysis of DOR (using all randomized patients; from the start of response to disease progression), DOR was significantly longer for patients in the fulvestrant group compared with patients in the anastrozole group. Both drugs were tolerated well; withdrawals due to drug-related adverse events were 0.9% and 1.2% in the fulvestrant group and the anastrozole group, respectively. The incidence of joint disorders was significantly lower in the fulvestrant group (P=0.0036). CONCLUSIONS: Fulvestrant was tolerated well and was at least as effective as anastrozole in the second-line treatment of patients with ABC. This new hormonaltherapy may provide a valuable treatment option for ABC in postmenopausal women.

Adult↗
PubMed2003

Pharmacokinetics of a single dose of fulvestrant prolonged-release intramuscular injection in postmenopausal women awaiting surgery for primary breast cancer.

OBJECTIVE: The aim of this study was to describe the pharmacokinetics of 3 different single doses of fulvestrant-a new estrogen receptor (ER) antagonist that downregulates the ER with no known agonist effects-administered as a prolonged-release IM formulation. METHODS: Pharmacokinetic data were obtained in a randomized, partially blinded, placebo-controlled, parallel-group, Phase I/II multicenter trial involving postmenopausal women with primary breast cancer (clinical stages T1-T3, with tumors that were ER positive or of unknown ER status) awaiting curative-intent surgery. Patients received either IM fulvestrant (50, 125, or 250 mg), oral tamoxifen (20 mg, once daily), or oral placebo (once daily). Treatment started 2 to 3 weeks before surgery and blood was taken at various times up to 12 weeks after fulvestrant administration to assess pharmacokinetic variables. RESULTS: A total of 200 patients entered the trial, of whom 58 took part in the pharmacokinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). Following single IM injections of fulvestrant, the median time to maximum concentration was 6.98, 6.98, and 6.96 days in the 50-, 125,- and 250-mg dose groups, respectively, with an overall range of 2 to 19 days). The plasma concentration-time profiles were primarily controlled by the rate of absorption from the injection site; post-peak plasma concentrations declined over time and were measurable up to 84 days after administration of fulvestrant 125 and 250 mg. Plasma concentrations at 28 days were 2- to 5-fold lower than the maximum value. Plasma concentration data for the 250-mg dose were best described by a 2-compartment pharmacokinetic model, with an apparent terminal phase half-life of approximately 49 days, beginning approximately 3 weeks after administration. Mean area under the plasma concentration-time curve for days 0 through 28 (AUC 0-28) was proportional for fulvestrant 50, 125, and 250 mg. For a doubling of the dose, an analysis of covariance model of the pharmacokinetic data projected an estimated increase in AUC 0-28 of a factor of 1.84 (95% CI, 1.67 to 2.04). CONCLUSIONS: The IM formulation of fulvestrant used in this study had predictable, dose-linear pharmacokinetics. The prolonged-release properties of this formulation suggested that it may be well suited for the once-monthly dosing schedule intended for clinical use.

Aged↗
PubMed2002

An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane.

BACKGROUND: The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles. METHODS: In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. RESULTS: At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, respectively. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. CONCLUSIONS: All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clinical significance of these differences remains to be elucidated.

Anastrozole↗