Therapy For Advanced Breast Cancer Research Articles

Docetaxel and mitoxantrone, versus docetaxel mitoxantrone and letrozole as first-line therapy in advanced breast cancer: A randomized study

722 Background: Doxetaxel (DCT) and mitoxantrone (MX) are highly active and potentially synergistic agents in the treatment of metastatic breast cancer (MBC). Letrozole, a nonsteroidal, third-generation aromatase inhibitor has shown efficacy in the treatment of postmenopausal women with advanced disease, producing objective tumor response rates of approximately 25% after failure of previous therapy. This study evaluates the combination of DCT and MX with or without letrozole in patients with MBC to determine the efficacy and toxicity of this therapy. Methods: One hundred and eleven (median age 62 yrs), postmenopausal previously untreated patients with MBC were studied. The patients were randomly assigned to receive the combination of Docetaxel 80 mg/m2, Mitoxantrone 12 mg/m2 every three weeks and Letrozole 2.5 mg daily (group A, n=56 pts), or Docetaxel 80 mg/m2 and Mitoxantrone 12 mg/m2, every three weeks (group B, n=55 pts). Response was assessed according to UICC criteria at 12 and 24 weeks. Results: The treatment with DCT and MX was well tolerated. Toxicity was low in both arms, without statistical difference: 24 grade I and 18 grade 2 cases were observed in Group A vs 22 grade I and 17 grade 2 cases in group B. At 24 weeks, complete remissions were seen in 9.8% of group B and 5.8% of group A, partial remissions were observed in 58.8% and 53 %, respectively; and stable disease was achieved in 9.8% and 13.7%, respectively. Disease progressed in 21.5% of group B patients and 27.4% of group A patients. None of these differences were significant Conclusions: Intensifying standard docetaxel and mitoxantrone first-line therapy in advanced breast cancer patients with letrozole hormone therapy may be of little benefit in terms of response rate. However, in the chemotherapy-hormonotherapy combination arm, there is a trend for more objective responses. No significant financial relationships to disclose.

Compassionate use of fulvestrant: Experience from the Institut Bergonié

746 Background: Fulvestrant (‘Faslodex’) is a new type of estrogen receptor antagonist with no known agonist effects. The fulvestrant Compassionate Use Program (CUP) enables its use in patients after progression on previous endocrine treatments and chemotherapies for advanced breast cancer (ABC). Method: As part of the CUP, we treated 41 women and one man with fulvestrant between August 2001 and September 2004. In accordance with rules imposed by the French Drug Agency (AFSSAPS), fulvestrant could only be used after most other endocrine treatments had been prescribed. Permission was given for the use of fulvestrant in each case. Results: Our patients had a median age of 65 years (range 41–86). All patients had advanced disease, including 19 patients with visceral metastases (liver and lung) and 25 with bone metastases. Adjuvant endocrine treatment (tamoxifen) followed primary surgery in 16 cases, and 3 patients received adjuvant chemotherapy. Fulvestrant was given after a median of 3 (range: 1–5) prior endocrine treatments and a median of 1 prior (range: 0–5) chemotherapy for ABC. Twelve patients achieved a partial response (PR) on fulvestrant therapy, and 10 experienced stable disease ≥6 months (SD), giving a clinical benefit (CB) rate of 52%. Fulvestrant was used as 2nd-line ABC therapy in 6 patients, with a CB rate of 83% (2 PR, 3 SD). The remaining 36 patients received fulvestrant as 3rd to 9th-line treatment for ABC (CB rate = 47%; 10 PR, 7 SD). In patients with visceral metastases the CB rate was 58% (6 PR, 5 SD). Across all patients, median duration of treatment was 5 months (range: 1–38). Currently, 19 patients are deceased, 2 are receiving further endocrine therapy (progestins) and 21 are receiving palliative chemotherapy. Fulvestrant was well tolerated; 6 patients (14%) reported adverse events as a result of treatment. Conclusion: In our institution, fulvestrant demonstrated good efficacy when given after other endocrine treatments and chemotherapies. The CB rate appeared to be higher when fulvestrant (which is approved for 2nd-line use), was given early in the therapy sequence; however, efficacy was retained in more heavily pre-treated patients. Patients with visceral metastases also gained clinical benefit from fulvestrant. No significant financial relationships to disclose.

Aromatase inhibitors for therapy of advanced breast cancer

In postmenopausal women with advanced breast cancer, numerous phase III trials have been performed comparing the third-generation non-steroidal aromatase inhibitors (NS-AIs) anastrozole and letrozole and the steroidal AI (S-AI) exemestane in the “first-line” setting against tamoxifen and in the “second-line” setting against megestrol acetate. In both settings, the AIs were at least as efficacious or superior in some endpoints with a preferable toxicity profile including a lower incidence of thrombotic events. Relatively small differences in potency between the three AIs have been identified and it has not been demonstrated that these differences have clinical implications. The recent establishment of the value of AIs in the adjuvant setting for postmenopausal women will impact on their utilization in advanced disease. In premenopausal women the third-generation AIs have not been studied as monotherapy and there is a paucity of data in combination with ovarian function suppression in the advanced disease setting. The main area of future investigations for the AIs in premenopausal women will be in the adjuvant therapy setting in combination with suppression of ovarian function.

Comparison of Pre- and Postsurgical Concentrations of Blood HER-2 mRNA and HER-2 Extracellular Domain Reflects HER-2 Status in Early Breast Cancer

The HER-2 gene (HER-2/neu or c-erbB-2) encodes an 185-kDa transmembrane glycoprotein that is a member of the type I family of growth factor receptors. HER-2 is constitutively activated by overexpression and contributes to cell growth, angiogenesis, survival, and metastasis (1). The assessment of HER-2 status in breast carcinomas provides valuable prognostic and predictive information. Immunohistochemistry, fluorescence in situ hybridization, chromosomal in situ hybridization, and quantitative reverse transcription-PCR (RT-PCR) may be used for this purpose. Other approaches have been proposed for the assessment of HER-2 status in peripheral blood, including evaluating either circulating HER-2 extracellular domain (ECD) or nucleated cell-associated HER-2 mRNA. Some studies have indicated that circulating ECD/HER-2 is frequently increased in metastatic disease (2)(3)(4). In addition, high concentrations of ECD/HER-2 are associated with cancer aggressiveness (5) and predict response to trastuzumab (6)(7)(8) and antiestrogen (4) therapies in advanced breast cancer. Recently, Martin et al. (9), using an array to assess circulating mRNA, pointed out that HER-2 mRNA was generally low in the blood of healthy individuals but was increased in 31% of patients with untreated invasive breast cancer. Almost all of these studies evaluated blood markers in patients with advanced or metastatic breast cancer using a single presurgical sample. Our study included 40 consecutive patients (median age, 58 years; range, 29–80 years) undergoing surgery for early breast cancer. Patients did not receive any systemic therapy before surgery and provided informed consent for the study. According to tumor size, 28 patients were classified as T1, whereas the remaining 12 were T2 or T3. Twenty-two were node negative, and 35 were positive for estrogen receptors. From each patient, we collected 12 mL of venous blood in EDTA tubes and divided the blood into two 5-mL aliquots. The first was centrifuged, and the plasma …

Paclitaxel in a novel formulation containing less Cremophor EL as first-line therapy for advanced breast cancer: A phase II trial

Paclitaxel (Taxol) is formulated in 50% Cremophor EL (CrEL)/absolute ethanol for clinical use. In order to reduce vehicle-related side effects, Genetaxyl was developed to have paclitaxel formulated in a solution containing lesser amounts of CrEL and ethanol plus 2 other solvents. The purpose of the study was to evaluate the efficacy and safety of Genetaxyl as first-line therapy to treat breast cancer patients. Patients with newly diagnosed stage III (N = 8) or IV (N = 10), or recurrent (N = 11) breast cancer received single-agent Genetaxyl at 175 mg/m(2) administered in a 3-h infusion every 3 weeks for 3-6 cycles. A total of 148 cycles were delivered to 29 patients. The overall response rate was 41.4% (95% confidence interval, 23.4 to 59.2%), and that of patients with metastatic disease (N = 20) was 30%. Median survival for all patients was 32.4 months and 24.3 months for patients having metastatic disease. The toxicity profile seems favorable, especially regarding myelosuppression and myalgia/arthralgia. No severe hypersensitivity reaction occurred. These phase II trial results demonstrate that a 60% reduction of CrEL by Genetaxyl's formulation does not affect the activity of paclitaxel and could allow for better control of several CrEL-related toxicities.

Preclinical and Clinical Experience with Fulvestrant (Faslodex) in Postmenopausal Women with Hormone Receptor-Positive Advanced Breast Cancer

Fulvestrant (Faslodex) is a new type of estrogen receptor (ER) antagonist that binds, blocks, and degrades the ER, leading to reduced expression of the progesterone receptor (PgR). Unlike the selective ER modulator tamoxifen, fulvestrant is devoid of any known agonist activity. Fulvestrant has a steroidal structure that competitively binds to the ER with an affinity much greater than that of tamoxifen. After binding to fulvestrant, degradation of the ER is accelerated, ultimately resulting in a reduction in cellular ER. Immunohistochemical studies have demonstrated that a single intramuscular injection of fulvestrant results in a dose-dependent decrease in ER and PgR indices and in Ki-67 expression. At the approved 250 mg dose, the decrease in receptor positivity with fulvestrant treatment was greater than that with tamoxifen. Phase III clinical trials have demonstrated the clinical benefit of fulvestrant in the endocrine treatment of breast cancer. Among patients who progressed during adjuvant or first-line endocrine therapy, fulvestrant was at least as effective as anastrozole as second-line treatment for the primary endpoints of objective response and time to progression, and was well tolerated. After a median follow-up of 24.5 months, a combined survival analysis from two Phase III studies has shown that fulvestrant may be considered similar to anastrozole for time to death (27.4 months versus 27.7 months, respectively). For the first-line therapy of advanced breast cancer in postmenopausal women, fulvestrant was shown to be active and well tolerated in a trial that compared fulvestrant 250 mg once monthly and tamoxifen 20 mg once daily. Treatment with fulvestrant has also demonstrated clinical efficacy among patients who progressed following treatment with tamoxifen followed by nonsteroidal aromatase inhibitors. The efficacy of fulvestrant in sequential endocrine therapy and in combination with other agents appears promising and active investigations are ongoing to explore the clinical potential of this novel antiestrogen.

Endocrine treatment options for advanced breast cancer – the role of fulvestrant

For many years, tamoxifen has been the ‘gold standard’ amongst anti-oestrogen therapies for breast cancer. However, the selective aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, have demonstrated advantages over tamoxifen as first-line treatments for advanced disease. Anastrozole is also more effective as an adjuvant treatment in early, operable breast cancer and is being increasingly used in the adjuvant setting. Generally, the selective oestrogen receptor modulators (SERMs), such as toremifene, droloxifene, idoxifene, raloxifene, and arzoxifene, show minimal activity in tamoxifen-resistant disease and show no superiority over tamoxifen as first-line treatments. In addition to these agents, other treatment options for advanced disease include high-dose oestrogens and progestins. Response rates for high-dose oestrogens and tamoxifen are similar, but the use of oestrogens is limited by their toxicity profile. Consequently, there is a need for new endocrine treatment options for breast cancer, particularly for use in disease that is resistant to tamoxifen or AIs. Fulvestrant (‘Faslodex’) is a new type of steroidal oestrogen receptor (ER) antagonist that downregulates cellular levels of the ER and progesterone receptor and has no agonist activity. This paper reviews the key efficacy and tolerability data for fulvestrant in postmenopausal women in the context of other endocrine therapies and explores the potential role of fulvestrant within the sequencing of endocrine therapies for advanced breast cancer.

Aromatase inhibitors in advanced breast cancer

The third-generation aromatase inhibitors suppress whole-body estrogen production in postmenopausal women with high specificity and potency. In women with hormone-sensitive breast cancer, three of these agents, letrozole, anastrozole, and exemestane, provide an important alternative endocrine therapy to the antiestrogen tamoxifen, which blocks estrogen activation of the estrogen receptor. For treatment of advanced or metastatic breast cancer that has progressed on first-line tamoxifen, all three agents are active. On that basis, they have each been compared with tamoxifen as first-line therapy of advanced breast cancer, in phase III trials. Letrozole was significantly superior to tamoxifen in the primary end point, median time to progression, as well as in response rate and clinical benefit rate, and treatment was well tolerated. Although there was no significant difference in median overall survival, an advantage seen with letrozole for the first 2 years may have been lost because of crossover to the alternate agent at disease progression. Anastrozole was evaluated in two separate trials designed for combined analysis. Overall, anastrozole was at least equivalent to tamoxifen in activity, but clearly superior only for median time to progression in the subgroup of patients with hormone receptor-positive disease. Treatment was generally as well tolerated as tamoxifen. In an early report, exemestane was significantly better than tamoxifen in response rate and median time to progression, with overall survival data not yet available. To date, letrozole appears to be the most effective aromatase inhibitor in the first-line advanced breast cancer setting.

Phase III Study of Letrozole Versus Tamoxifen As First-Line Therapy of Advanced Breast Cancer in Postmenopausal Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group

Purpose: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. Patients and Methods: This multicenter phase III trial randomly assigned 916 patients with hormone receptor–positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician’s discretion. This report updates efficacy at a median follow-up of 32 months. Results: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P < .0001), time to treatment failure (median, 9 v 5.7 months, respectively; P < .0001), overall objective response rate (32% v 21%, respectively; P = .0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not signifi...

Tamoxifen--what next?

Most patients with advanced breast cancer (ABC) ultimately die due to disease progression. Consequently, treatments for ABC are predominantly palliative in nature and, therefore, the tolerability profile of a given treatment is particularly relevant in these patients. While cytotoxic chemotherapy and endocrine therapy exhibit efficacy in hormone-sensitive, advanced disease, it is endocrine therapy that combines efficacy with minimal acute toxicity. Tamoxifen has been the chosen endocrine therapy for postmenopausal, hormone-sensitive, ABC for over 20 years. More recently, new endocrine agents with different mechanisms of action from tamoxifen have been introduced. Evidence indicates that the aromatase inhibitors anastrozole (Arimidex; AstraZeneca; Wilmington, DE), letrozole (Femara; Novartis Pharmaceuticals Corp.; East Hanover, NJ) and exemestane (Aromasin; Pharmacia Corp.; Peapack, NJ) offer superior efficacy and tolerability to tamoxifen in the first-line treatment of postmenopausal, hormone-sensitive ABC. Similarly, after tamoxifen failure, fulvestrant (Faslodex; AstraZeneca), a new estrogen receptor (ER) antagonist that downregulates the ER, is at least as effective as anastrozole, is well tolerated, and is not cross-resistant with tamoxifen. Unlike tamoxifen, fulvestrant has no known agonist effects. The sequential use of such agents may prolong the time during which endocrine therapies can be used, thereby avoiding the more acute toxicities associated with cytotoxic chemotherapy. Indeed, a series of studies has shown that this sequential use is a relevant, active, and well-tolerated option. Establishing the comparative efficacies and optimal sequences that incorporate the newer endocrine agents will be central in determining the future role of hormonal therapy in ABC; the results of this work will determine the relative place of tamoxifen in what is a rapidly changing therapeutic environment.

Systemic therapy for advanced breast cancer.

An intriguing, yet highly logical area of research for breast cancer therapy is the exploration of growth factor pathways. Areas of investigation include epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) targeting. Although results of these studies to date have been less than promising, they have yielded important insights into critical factors that must be taken into consideration when devising growth factor-targeted therapies. Even though the results of EGFR and VEGF studies have not met with expectations, several preclinical models assessing new combinations of biologic agents with either hormonal therapy or chemotherapy are beginning to show promise.

Targeted Therapy for Cancer

The recent approval in the US and Europe of imatinib (Gleevac™) for patients with bcr/abl-positive chronic myelogenous leukemia and the considerable public interest in new anticancer drugs that take advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatment are driving a new era of integrated diagnostics and therapeutics. This review highlights the history of targeted anticancer therapies with a focus on the development of molecular diagnostics for hematologic malignancies and the emergence of trastuzumab (Herceptin™)-based therapy for advanced breast cancer. The potential of pharmacogenomic strategies and the use of high-density genomic microarrays to classify and select therapy for cancer are emphasized. This review also considers the widely held view that, in the next 5–10 years, the clinical application of molecular oncology and molecular diagnostics will further revolutionize the drug discovery and development process, customize the selection, dose and route of administration of existing and new therapeutic agents, and truly personalize medical care for cancer patients.

The complex between urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-I) independently predicts response to first-line endocrine therapy in advanced breast cancer.

It has been shown that urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-I) have predictive value for therapy success in advanced breast cancer. Levels of the complex between uPA and PAI-I, formed when both molecules are in their active form, might have superior predictive power. Here, we investigate the association between levels of uPA:PAI-I complex and rate of response to first-line systemic therapy for advanced breast cancer. Tumor tissues of 170 patients with advanced breast cancer were analyzed for uPA:PAI-I complex concentrations using a quantitative enzyme-linked immunosorbent assay. The patients received either endocrine therapy (n=96) or chemotherapy (n=74) as first-line treatment after diagnosis of advanced disease. Of the endocrine treated patients, those with high levels of uPA:PAI-I complex showed a shorter progression-free survival (PFS) compared to patients with lower uPA:PAI-I complex levels (P=0.035). Furthermore, in the multivariate regression analysis a significant lower rate of response to first-line endocrine therapy was found in patients with high uPA:PAI-I complex levels compared to patients with low uPA:PAI-I complex levels (odds ratio (OR)=0.27, 95% CI, 0.09-0.59, P=0.018), in addition to the predictive impact of the steroid hormone receptor (ER/PgR) status (OR=2.68, 95% CI, 1.08-6.63, P=0.033). Complex levels did not predict efficacy of chemotherapy in patients with advanced breast cancer. The results show that the plasminogen activation system affects the response to endocrine therapy independent of steroid hormone receptor status and may be of help to further refine the indication for this treatment in individual patients. Further studies are warranted to explain this underlying resistance to endocrine therapy when uPA:PAI-I levels are high.

A trial-based cost-effectiveness analysis of letrozole followed by tamoxifen versus tamoxifen followed by letrozole for postmenopausal advanced breast cancer

BackgroundThird-generation aromatase inhibitors are being considered as an alternative to tamoxifen as first-line therapy for advanced breast cancer. These newer therapies are more expensive, and will gain greater acceptance if they can demonstrate cost-effectiveness. MethodsLife table analyses are used to compare the costs and benefits [life years gained and quality-adjusted life years (QALYs) gained] of treating postmenopausal women with advanced breast cancer with first-line letrozole (with the option of second-line tamoxifen) compared with first-line tamoxifen (with the option of second-line letrozole). Patient-level data from a large clinical trial describes the effectiveness of the therapy options, clinicians estimate resource usage and utility values are obtained from the literature. ResultsThe mean cost of providing first- and second-line hormonal therapy is £4765 if letrozole is the first-line therapy and £3418 if tamoxifen is provided first (a difference of £1347). However, patients receiving letrozole as first-line therapy gain an additional 0.228 life years, or 0.158 QALYs. The cost-effectiveness analysis found that first-line hormonal therapy with letrozole gains additional life years at a cost of £5917, whilst the cost per additional QALY gained is £8514. ConclusionThe strategy of letrozole as first-line hormonal therapy not only provides an opportunity for extending and improving patient’s quality of life, but also is highly cost-effective compared with other generally accepted medical treatments.

Combined hormonal therapy for advanced breast cancer in postmenopausal patients

The primary therapeutic goal for patients with locally recurrent, locally advanced, or metastatic breast cancer is retarding the progression of cancer for as long as possible, while minimizing side effects and maintaining good quality of life. The majority of breast cancers have nuclear receptors for estrogen (ER) and/or progesterone (PR) and utilize estrogen as a major growth factor. Antagonizing estrogen to control tumor growth has been achieved in two ways: by competing for the binding site of the estrogen receptor with anti-estrogens (SERMS) or by removing estrogen by inhibiting its synthesis with aromatase (estrogen synthetase) inhibitors (AIs). Cancer cells develop resistance to SERMS such as tamoxifen (Nolvadex®) or toremifene (Fareston®) by increasing uptake of estrogens from plasma, by developing hypersensitivity to the residual level of ER stimulation and by increasing levels of estrogen synthesizing enzymes, such as aromatase, within the tumor cells as much as 3–10 fold. High in-situ, intra- and peri-tumoral estrogen levels may displace the SERM and cause clinical progression of the disease. In contrast resistance to AI therapy may also develop by causing hypersensitivity to residual and exogenous estrogens. Hence it has been hypothesized that a combination of a SERM and an AI (total estrogen blockade) might be the optimal way to treat hormone dependent breast cancer and prevent the emergence of resistance. Combining tamoxifen (SERM) with an AI (anastrozole) was one of three arms of the Phase 3 adjuvant ATAC study comparing tamoxifen to anastrozole and the combination. Interestingly the combination arm performed worst of all, the hypothesis being that in the low estrogenic environment created by the AI, tamoxifen exaggerates its known partial estrogenic signal. It has been hypothesized that if a SERM with less inherent estrogenicity than tamoxifen were combined with an AI the therapy would be more successful. Similar to letrozole and tamoxifen combined in another trial, a 27% reduction in plasma levels of anastrozole was also detected. BioMedicines is currently testing that hypothesis in a clinical Phase 3 trial combining the experimental and currently unapproved AI atamestane and the approved SERM toremifene and comparing that combination to the approved AI letrozole. Toremifene is clinically equi-effective against tamoxifen in treatment naive patients, but is 40-fold less estrogenic in a low estrogen environment in preclinical models. Atamestane is a steroidal AI, which has shown a median time to progression of 8 months, with 10% of the patients progression-free at 36 months, in tamoxifen-resistant patients. It is well tolerated and may have advantages over the non-steroidal AI's in terms of efficacy and toxicity. Atamestane also does not interact pharmacologically with the toremifene. The control arm is letrozole, currently the most effective single agent endocrine therapy for postmenopausal women. Patients eligible for our study are required to have positive receptor status, have measurable tumor lesions and to have received the last dose of adjuvant hormonal therapy at least 12 months prior to enrollment. Our trial strategy is thus similar to the total androgen blockade approach to prostate cancer where this approach has been successful.

Metabolism of medroxyprogesterone acetate (MPA) via CYP enzymes in vitro and effect of MPA on bleeding time in female rats in dependence on CYP activity in vivo

Medroxyprogesterone acetate (MPA) is a drug commonly used in endocrine therapy for advanced breast cancer, although it is known to cause thrombosis as a serious side effect. Recently, we found that cytochrome P450 3A4 (CYP3A4) mainly catalyzed the metabolism of MPA via CYP in human liver microsomes. However, the metabolic products of MPA in humans and rats have not been elucidated. In addition, it is not clear whether thrombosis could be induced by MPA itself or by its metabolites. In this study, we determined the overall metabolism of MPA as the disappearance of the parent drug from an incubation mixture, and identified the enzymes catalyzing the metabolism of MPA via CYP in rats. Moreover, the effects of CYP-modulators on MPA-induced hypercoagulation in vivo were examined. Intrinsic clearance of MPA in rat liver microsomes was increased by treatment with CYP3A-inducers. The intrinsic clearance of MPA in liver microsomes of rats treated with various CYP-inducers showed a significant correlation with CYP3A activity, but not CYP1A activity, CYP2B activity or CYP2C contents. Among the eight recombinant rat CYPs studied, CYP3A1, CYP3A2 and CYP2A2 catalyzed the metabolism of MPA. However, since CYP3A2 and CYP2A2 are male-specific isoforms, CYP3A1 appears to be mainly involved in the metabolism of MPA in liver microsomes of female rats. In an in vivo study, pretreatment of female rats with SKF525A, an inhibitor of CYPs including CYP3A1, significantly (p < 0.05) enhanced MPA-induced hypercoagulation, whereas pretreatment with phenobarbital, an inducer of CYPs including CYP3A1, reduced it. These findings suggest that CYP-catalyzed metabolism of MPA is mainly catalyzed by CYP3A1 and that MPA-induced hypercoagulation is predominantly caused by MPA itself in female rats.

An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole

It was previously shown that letrozole (Femara®) was significantly more potent than anastrozole (Arimidex®) in inhibiting aromatase activity in vitro and in inhibiting total body aromatisation in patients with breast cancer. The objective of this study was to compare letrozole (2.5 mg per day) and anastrozole (1 mg per day) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-oestrogen. This randomised, multicentre and multinational open-label phase IIIb/IV study enrolled 713 patients. Treatment was for advanced breast cancer that had progressed either during anti-oestrogen therapy or within 12 months of completing that therapy. Patients had tumours that were either positive for oestrogen and/or progesterone receptors (48%) or of unknown receptor status (52%). The primary efficacy endpoint was time to progression (TTP). Secondary endpoints included objective response, duration of response, rate and duration of overall clinical benefit (responses and long-term stable disease), time to treatment failure, and overall survival, as well as general safety. There was no difference between the treatment arms in TTP; median times were the same for both treatments. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) (19.1% versus 12.3%, P=0.013), including in predefined subgroups (receptor status-unknown, and soft-tissue- and viscera-dominant site of disease). There were no significant differences between the treatment arms in the rate of clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure or overall survival. Both agents were well tolerated and there were no significant differences in safety. These results support previous data documenting the greater aromatase-inhibiting activity of letrozole and indicate that advanced breast cancer is more responsive to letrozole than to anastrozole as second-line endocrine therapy.

Non-endocrine systemic therapies in advanced breast cancer

Non-endocrine systemic therapies in advanced breast cancer

Anastrozole (Arimidex™) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results

We present an initial survival analysis and an update of the safety data of the North American and Tamoxifen or Arimidex™ Randomized Group Efficacy and Tolerability (TARGET) double-blind, randomised, multicentre studies which compared anastrozole with tamoxifen as first-line treatment in postmenopausal patients with oestrogen receptor and/or progesterone receptor-positive (ER+/PR+) or receptor-unknown advanced breast cancer (ABC). At a median follow-up of 43.7 months, 56.0% of patients in the anastrozole group and 56.1% of patients in the tamoxifen group had died. The proportion of patients dead at 2 years was 31.1 and 32.0% in the anastrozole and tamoxifen groups, respectively. In the ER+/PR+ subgroup, 55.1 and 55.9% of patients had died and median time to deaths (TTD) were 40.8 and 41.3 months in the anastrozole and tamoxifen groups, respectively. Both agents remained well tolerated, with fewer reports of vaginal bleeding (anastrozole versus tamoxifen, 1.0% versus 2.5%) and thromboembolic events (anastrozole versus tamoxifen, 5.3% versus 9.0%) in the anastrozole group versus the tamoxifen group. Hot flushes and vaginal dryness were reported marginally less in the tamoxifen group compared with the Anastrozole group. Although no improvement in survival was observed, the favourable profile of anastrozole with respect to efficacy (TTP) and tolerability [Cancer 92 (2001) 2247] support the use of anastrozole in advance of tamoxifen as the first-line therapy choice in postmenopausal women with ABC.

Polyneuroendocrine therapy of advanced breast cancer with LHRH analogue, tamoxifen and the antiprolactinemic drug cabergoline: Phase 2 study

Polyneuroendocrine therapy of advanced breast cancer with LHRH analogue, tamoxifen and the antiprolactinemic drug cabergoline: Phase 2 study