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Vered Stearns - One of the best experts on this subject based on the ideXlab platform.

  • Effect of simvastatin on the pharmacokinetics of Anastrozole.
    Breast cancer research and treatment, 2011
    Co-Authors: Ting Bao, Amanda L. Blackford, Vered Stearns
    Abstract:

    We have prospectively tested the effects of simvastatin on the pharmacokinetics of Anastrozole and on estrogen concentrations in postmenopausal women with hormone receptor-positive breast cancer who were receiving adjuvant Anastrozole. Following 14 days of simvastatin, we did not observe a significant change in plasma concentrations of Anastrozole or hydroxyAnastrozole in nine evaluable women. Likewise, we did not observe any statistically significant change in serum concentrations of either estradiol, which remained in the undetectable range, or estrone sulfate. Simvastatin and Anastrozole may be safely co-administered. Pharmacokinetic results suggest that simvastatin is not likely to compromise the activity of Anastrozole.

  • In Vitro and In Vivo Oxidative Metabolism and Glucuronidation of Anastrozole
    British journal of clinical pharmacology, 2010
    Co-Authors: Landry K. Kamdem, Yong Liu, Vered Stearns, Susan Kadlubar, Jacqueline Ramírez, Stacie Jeter, Karineh Shahverdi, Bryan A. Ward, Evan T. Ogburn, Mark J. Ratain
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Anastrozole is primarily cleared by hepatic metabolism via oxidative and conjugating enzymes. WHAT THIS STUDY ADDS • Anastrozole is oxidized to hydroxyAnastrozole mainly by CYP3A4/5 and glucuronidated to Anastrozole glucuronide predominantly by UGT1A4 in vitro. • HydroxyAnastrozole glucuronide and hydroxyAnastrozole were quantified as the major metabolites of Anastrozole in plasma of breast cancer patients. • This study describes for the first time Anastrozole metabolic pathways and the enzymes involved, which may serve as the scientific basis for pharmacogenetic and drug-interaction assessments. AIMS Little information is available regarding the metabolic routes of Anastrozole and the specific enzymes involved. We characterized Anastrozole oxidative and conjugation metabolism in vitro and in vivo. METHODS A sensitive LC-MS/MS method was developed to measure Anastrozole and its metabolites in vitro and in vivo. Anastrozole metabolism was characterized using human liver microsomes (HLMs), expressed cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs). RESULTS HydroxyAnastrozole and Anastrozole glucuronide were identified as the main oxidative and conjugated metabolites of Anastrozole in vitro, respectively. Formation of hydroxyAnastrozole from Anastrozole was markedly inhibited by CYP3A selective chemical inhibitors (by >90%) and significantly correlated with CYP3A activity in a panel of HLMs (r= 0.96, P= 0.0005) and mainly catalyzed by expressed CYP3A4 and CYP3A5. The Km values obtained from HLMs were also close to those from CYP3A4 and CYP3A5. Formation of Anastrozole glucuronide in a bank of HLMs was correlated strongly with imipramine N-glucuronide, a marker of UGT1A4 (r= 0.72, P < 0.0001), while expressed UGT1A4 catalyzed its formation at the highest rate. HydroxyAnastrozole (mainly as a glucuronide) and Anastrozole were quantified in plasma of breast cancer patients taking Anastrozole (1 mg day−1); Anastrozole glucuronide was less apparent. CONCLUSION Anastrozole is oxidized to hydroxyAnastrozole mainly by CYP3A4 (and to some extent by CYP3A5 and CYP2C8). Once formed, this metabolite undergoes glucuronidation. Variable activity of CYP3A4 (and probably UGT1A4), possibly due to genetic polymorphisms and drug interactions, may alter Anastrozole disposition and its effects in vivo.

  • Effect of simvastatin on the pharmacokinetics of Anastrozole
    Journal of Clinical Oncology, 2009
    Co-Authors: Ting Bao, Stacie Jeter, Michelle A Rudek, Zeruesenay Desta, Amanda L. Blackford, Shannon Slater, L. Wright, Vered Stearns
    Abstract:

    1517 Background: When used in the adjuvant setting, aromatase inhibitors (AIs) reduce the incidence of contralateral breast cancer and are therefore under investigation for primary breast cancer prevention. Statins hold promise for chemoprevention based on preclinical and epidemiological data. Adding statin to AI has the potential to enhance breast cancer prevention and to protect women from AI-related side effects. Prior to initiating a chemoprevention trial of combination therapy, we evaluated the potential for pharmacokinetic drug-drug interaction between Anastrozole and simvastatin in postmenopausal women taking adjuvant Anastrozole to ensure that the combination will not influence Anastrozole concentration or affect its ability to reduce estrogen. Methods: Postmenopausal women with hormone receptor-positive, stage 0-III breast cancer who had been on adjuvant Anastrozole (1 mg/day) for at least 30 days were prescribed 14 days of simvastatin (40 mg/day). We collected serum at baseline (Anastrozole alon...

Aman U Buzdar - One of the best experts on this subject based on the ideXlab platform.

  • Anastrozole aromatase inhibitor plasma drug concentration genome wide association study functional epistatic interaction between slc38a7 and alppl2
    Clinical Pharmacology & Therapeutics, 2019
    Co-Authors: Tanda M Dudenkov, Aman U Buzdar, James N. Ingle, Mark E. Robson, Junmei Cairns, Duan Liu, Sandhya Devarajan, Yongxian Zhuang, Michiaki Kubo, Anthony Batzler
    Abstract:

    Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma Anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an Anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an Anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and Anastrozole plasma concentrations.

  • Variation in Anastrozole Metabolism and Pharmacodynamics in Women with Early Breast Cancer
    Cancer research, 2010
    Co-Authors: James N. Ingle, Aman U Buzdar, Daniel J. Schaid, Matthew P. Goetz, Anthony Batzler, Mark E. Robson, Donald W. Northfelt, Janet E. Olson, Edith A. Perez, Zeruesenay Desta
    Abstract:

    Aromatase inhibitors play a prominent role in the management of postmenopausal women with endocrine-sensitive breast cancer, but there is large variability in both efficacy and tolerability. The purpose of our study was to define interindividual variation in Anastrozole metabolism and pharmacodynamics among patients treated with the approved daily dose of 1 mg in a standard practice setting as adjuvant therapy for resected early breast cancer. This study was performed in 191 women in whom pretreatment and during Anastrozole plasma concentrations of estrone (E1), estradiol (E2), estrone conjugates, androstenedione, and testosterone were determined and correlated with plasma concentrations of Anastrozole and Anastrozole metabolites. There were large interindividual variations in plasma Anastrozole and Anastrozole metabolite concentrations, as well as pretreatment and postdrug plasma E1, E2, and E1 conjugate and estrogen precursor (androstenedione and testosterone) concentrations. E1 and E2 concentrations were below the lower limit of quantitation (LLQ) in most patients after Anastrozole therapy (83% for both), but those with detectable concentrations had a broad range (1.58-45.2 and 0.635-97.0 pg/mL, respectively). E1 conjugates after Anastrozole therapy were above the LLQ in most patients (93%), with wide interpatient variability (3.50-2,990 pg/mL). Two patients seemed to extensively metabolize Anastrozole and failed to display substantial decreases in estrogens. Acknowledging the potential factor of variable compliance, our results showed large interindividual variation in Anastrozole metabolism and its effect on circulating estrogens in postmenopausal patients. These findings may have implications with regard to efficacy and adverse events and may indicate the need to "individualize" therapy with this drug.

  • Efficacy of tamoxifen following Anastrozole ('Arimidex') compared with Anastrozole following tamoxifen as first-line treatment for advanced breast cancer in postmenopausal women.
    European journal of cancer (Oxford England : 1990), 2003
    Co-Authors: B Thurlimann, Aman U Buzdar, John F.r. Robertson, J.m Nabholtz, J Bonneterre
    Abstract:

    Anastrozole ('Arimidex') is indicated for the treatment of advanced breast cancer in postmenopausal women. Combined analysis of two international randomised, double-blind trials (n=1021) showed that in patients with hormone receptor-positive tumours, first-line treatment with Anastrozole significantly prolonged the time to progression (TTP) compared with tamoxifen (median TTP: 10.7 versus 6.4 months, respectively; P=0.022). Second-line tamoxifen following Anastrozole, or vice versa, in this trial population was unblinded. The treatments were crossed over and then efficacy was assessed using a questionnaire. Of 511 patients randomised to Anastrozole, 137 (26.8%) received second-line tamoxifen. Questionnaire data were available for 119 patients; 58 (48.7%) gained clinical benefit (CB=complete+partial response (CR+PR)+(stable disease (SD) >/=24 weeks)), while 12 (10.1%) had an objective response (OR=CR+PR). Of 510 patients randomised to tamoxifen, 134 (26.3%) received second-line Anastrozole. Questionnaire data from 95 patients showed that 54 (56.8%) gained CB and 7 of the patients gaining CB (7.4%) had an OR. Previous studies showed Anastrozole is effective after first-line tamoxifen. These data show that the sequential administration of first-line Anastrozole followed by tamoxifen provides effective use of these drugs in the treatment of postmenopausal women with advanced breast cancer.

  • Anastrozole as Adjuvant Therapy for Early-Stage Breast Cancer: Implications of the ATAC Trial
    Clinical Breast Cancer, 2003
    Co-Authors: Aman U Buzdar
    Abstract:

    Tamoxifen has been the gold standard adjuvant therapeutic agent for postmenopausal women with hormone-sensitive breast cancer for > 25 years. Although it continues to play an important role in treating premenopausal women, tamoxifen's association with some serious safety and tolerability issues, including increased incidence of endometrial cancer and thromboembolic events, may be cause to limit its use in postmenopausal women. Anastrozole was the first drug to show improved efficacy and safety compared with standard therapies for first- and second-line therapy of hormone-sensitive advanced breast cancer in postmenopausal women. This article provides a review of the results of the first major analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) early-stage breast cancer trial, initiated in 1996, and discusses the implications for the use of Anastrozole in the adjuvant setting. This randomized, double-blind, multicenter trial compared tamoxifen (20 mg once daily) with Anastrozole (1 mg) alone and in combination with tamoxifen, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, early-stage breast cancer. The results of the ATAC trial show Anastrozole to be more effective and better tolerated than tamoxifen in this group of patients, and an updated follow-up suggests the therapeutic index for Anastrozole will continue to remain superior to that of tamoxifen. Anastrozole is now emerging as a new standard for the adjuvant treatment of postmenopausal women with hormone-sensitive early-stage breast cancer. New adjuvant trials are currently using Anastrozole in the control arm.

  • Anastrozole is superior to tamoxifen as first line therapy for advanced breast cancer in postmenopausal women results of a north american multicenter randomized trial
    Journal of Clinical Oncology, 2000
    Co-Authors: J.m Nabholtz, Alan Webster, Aman U Buzdar, M. Steinberg, Michael Pollak, W Harwin, G Burton, A Mangalik, M Von Euler
    Abstract:

    PURPOSE: The efficacy and tolerability of Anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) and tamoxifen were compared as first-line therapy for advanced breast cancer in 353 postmenopausal women. PATIENTS AND METHODS: The randomized, double-blind, multicenter study was designed to evaluate Anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with hormone receptor–positive tumors or tumors of unknown receptor status who were eligible for endocrine therapy. Primary end points were objective response (OR), defined as complete (CR) or partial (PR) response, time to progression (TTP), and tolerability. RESULTS: Anastrozole was as effective as tamoxifen in terms of OR (21% v 17% of patients, respectively), with clinical benefit (CR + PR + stabilization ≥ 24 weeks) observed in 59% of patients on Anastrozole and 46% on tamoxifen (two-sided P = .0098, retrospective analysis). Anastrozole had a significant advantage over tamoxifen in terms of TTP (medi...

Angela Brodie - One of the best experts on this subject based on the ideXlab platform.

  • Effect of selumetinib on the growth of Anastrozole-resistant tumors.
    Breast cancer research and treatment, 2013
    Co-Authors: Gauri Sabnis, Armina A. Kazi, Olga Golubeva, Preeti Shah, Angela Brodie
    Abstract:

    Despite significant improvement in the treatment outcome of hormone responsive postmenopausal breast cancer, some patients eventually acquire resistance to aromatase inhibitors (AIs). Using our MCF-7Ca xenograft model, we observed that although AIs such as Anastrozole initially inhibit tumor growth effectively, tumors eventually began to grow. Our previous data show that Anastrozole-resistant tumors upregulate growth factor receptor pathways as they adapt to grow in the low estrogen environment. Therefore, in the current study, we investigated the effect of inhibiting the growth factor receptor pathways with a MEK-1/2 inhibitor selumetinib (AZD6244, ARRY-142866). We treated the mice with Anastrozole-resistant tumors with selumetinib alone or in combination with Anastrozole. MCF-7Ca cells were inoculated sc into ovariectomized athymic nude mice supplemented throughout the experiment with androstenedione (100 μg/day), the substrate for aromatase conversion to estrogen. Once the tumors reached a measurable size (~300 mm3), the mice were treated with Anastrozole (200 μg/day), supplemented with androstenedione (Δ4A). The tumors in the Anastrozole group doubled in volume after 6 weeks, at which time the animals were regrouped to receive the following treatments: (i) Anastrozole, (ii) Anastrozole withdrawal (Δ4A alone), (iii) selumetinib (25 mg/kg/d, bid, po), and (iv) selumetinib + Anastrozole, (n = 10 mice/group). The treatments were given for 6 weeks (till week 12) and then the mice were euthanized, the tumors were collected and analyzed. The tumors of mice treated with selumetinib + Anastrozole had significantly lower growth rates than those treated with single agents (p = 0.008). Western blot analysis of the tumors showed that treatment with Anastrozole resulted in upregulation of proteins in the growth factor receptor cascade such as p-mTOR, pAkt, pMEK, and pMAPK. This was accompanied by downregulation of ERα protein, consistent with previous findings. The treatment of mice with selumetinib resulted in downregulation of activated MAPK, along with p-mTOR, which likely resulted in upregulation of ERα. Our results suggest that inhibition of the growth factor receptor pathway with selumetinib can reverse Anastrozole resistance.

  • Abstract 2919: Effect of selumetinib and AZD8055 on the growth of Anastrozole resistant tumors
    Endocrinology, 2012
    Co-Authors: Gauri Sabnis, Armina A. Kazi, Preeti Shah, Olga Goloubeva, Amanda Schech, Bob Zhang, Angela Brodie
    Abstract:

    Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Despite significant improvement in the treatment outcome of hormone responsive post-menopausal breast cancer, some eventually acquire resistance to AIs. Using our MCF-7Ca xenograft model, we observed that although, AI Anastrozole inhibited tumor growth, tumors eventually began to grow. Our previous data shows that Anastrozole resistant tumors upregulate growth factor receptor pathways as they adapt to grow in the low estrogen environment. In the current study, we investigated the effect of inhibiting the growth factor receptor pathways with two signal transduction inhibitors. We treated the mice with Anastrozole resistant tumors with selumetinib (AZD6244, ARRY-142866); an MEK 1/2 inhibitor and AZD8055; a dual mTORC1 and mTORC2 inhibitor, alone or in combination with Anastrozole. MCF-7Ca cells were inoculated sc into ovariectomized athymic nude mice supplemented with androstenedione (100 μg/d), the substrate for aromatase conversion to estrogen. Once the tumors reached a size of ∼300mm3, the mice were assigned to one of two treatment groups so that mean tumor volumes were not significantly different (p=0.98) at the start of treatment: control, Anastrozole (200μg/d). All animals continued to be supplemented with androstenedione (≥4A). The tumors in the Anastrozole group doubled after 6 weeks. At week 6, the animals were regrouped into six groups such that the mean tumor volumes were not significantly different (p=0.18). The mice received the following treatments (i) Anastrozole, (ii) Anastrozole withdrawal (≥4A alone), (iii) selumetinib (25mg/kg/d, bid, po), (iv) selumetinib + Anastrozole, (v) AZD8055 (20mg/kg/d, po), (vi) AZD8055 + Anastrozole (n=10 mice/group). The treatments were given for 6 weeks (till week 12) and then the mice were euthanized, tumors were collected and analyzed. Using mixed effects model, the growth rates of tumors (≥i) between different groups of treatments were compared. The tumors of mice treated with selumetinib + Anastrozole had significantly lower growth rate than both single agents (p=0.008). The growth rate of tumors of mice treated with AZD8055 + Anastrozole was marginally lower than the single agents (p=0.058). Western blotting analysis of the tumors showed that treatment with Anastrozole resulted in upregulation of proteins in the growth factor receptor cascade such as p-mTOR, pAkt, pMEK and pMAPK. This was accompanied by downregulation of ERα protein, consistent with previous findings. This suggests that Anastrozole resistance results in adaptation of the tumors to growth factor receptor pathway. When the tumors were treated with signal transduction inhibitors such as selumetinib or AZD8055, the respective pathways were effectively inhibited, which resulted in upregulation of ERα. Our results suggest that inhibition of growth factor receptor pathway with selumetinib or AZD8055 can reverse Anastrozole resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2919. doi:1538-7445.AM2012-2919

  • Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model
    Cancer research, 2008
    Co-Authors: Luciana Macedo, Gauri J. Sabnis, Olga G. Goloubeva, Angela Brodie
    Abstract:

    Although the aromatase inhibitor Anastrozole has been shown to be very effective in the treatment of hormone-dependent postmenopausal breast cancer, some patients with advanced disease will develop resistance to treatment. To investigate therapeutic strategies to overcome resistance to Anastrozole treatment, we have used an intratumoral aromatase model that simulates postmenopausal breast cancer patients with estrogen-dependent tumors. Growth of the tumors in the mice was inhibited by both Anastrozole and fulvestrant compared with the control tumors. Nevertheless, tumors had doubled in size at 5 weeks of treatment. We therefore investigated whether switching the original treatments to Anastrozole or fulvestrant alone or the combination of Anastrozole plus fulvestrant would reduce tumor growth. The results showed that the best strategy to reverse the insensitivity to Anastrozole or fulvestrant is to combine the two agents. Additionally, the tumors treated with Anastrozole plus fulvestrant from the beginning had only just doubled their size after 14 weeks of treatment, whereas the Anastrozole and fulvestrant treatments alone resulted in 9- and 12-fold increases in tumor size, respectively, in the same time period. Anastrozole plus fulvestrant from the beginning or in sequence was associated with down-regulation of signaling proteins involved in the development of hormonal resistance such as insulin-like growth factor type I receptor β, mitogen-activated protein kinase (MAPK), p-MAPK, AKT, mammalian target of rapamycin (mTOR), p-mTOR, and estrogen receptor α compared with tumors treated with Anastrozole or fulvestrant alone. These results suggest that blocking the estrogen receptor and aromatase may delay or reverse the development of resistance to aromatase inhibitors in advanced breast cancer patients. [Cancer Res 2008;68(9):3516–22]

Jean-marc Nabholtz - One of the best experts on this subject based on the ideXlab platform.

  • Anastrozole therapy for postmenopausal women with early breast cancer
    Expert Review of Obstetrics & Gynecology, 2007
    Co-Authors: Jean-marc Nabholtz
    Abstract:

    Although tamoxifen was the standard endocrine treatment for breast cancer for more than 30 years, aromatase inhibitors such as Anastrozole now have an important therapeutic role in postmenopausal women. Anastrozole gained initial acceptance for use in advanced breast cancer, but subsequent studies have shown that, in early breast cancer, Anastrozole is superior to tamoxifen as initial adjuvant therapy for newly diagnosed patients, while patients already receiving treatment benefit from switching to Anastrozole rather than continuing with tamoxifen or from extending therapy with Anastrozole after 5 years of tamoxifen. Additionally, in the neoadjuvant setting, Anastrozole may reduce tumor size in patients with locally advanced disease. Current studies are focusing on possible uses of Anastrozole in breast cancer prevention and combination treatments.

  • Role of Anastrozole across the breast cancer continuum: from advanced to early disease and prevention.
    Oncology, 2006
    Co-Authors: Jean-marc Nabholtz
    Abstract:

    Breast tumorigenesis is a continuum from preinvasive lesions to early breast cancer and advanced disease. In this article the data supporting the use of the aromatase inhibitor Anastrozole in postmenopausal women across this continuum are reviewed. In advanced disease, Anastrozole has a significant survival benefit and tolerability advantage compared with megestrol acetate when used as second-line treatment. As first-line therapy, Anastrozole significantly prolongs time to progression compared with tamoxifen in women with hormone receptor-positive (HR+) disease. In the adjuvant setting, Anastrozole has superior efficacy and tolerability compared with tamoxifen in newly diagnosed patients and those who have already received 2-3 years' prior adjuvant tamoxifen. Therefore, Anastrozole should be considered a preferred treatment option for postmenopausal women with HR+ early breast cancer. Furthermore, Anastrozole has preoperative efficacy in HR+ large or locally advanced tumors. Finally, Anastrozole substantially reduces the incidence of contralateral breast cancer compared with tamoxifen in women with HR+ early breast cancer and, therefore, is a potential chemopreventive agent. Anastrozole is thus positioned to become the standard care for postmenopausal women with HR+ disease across the whole breast cancer continuum. Additional data from ongoing studies will further clarify the role of Anastrozole across the continuum and answer outstanding questions regarding the optimal timing and duration of treatment.

  • Anastrozole arimidex versus tamoxifen as first line therapy for advanced breast cancer in postmenopausal women survival analysis and updated safety results
    European Journal of Cancer, 2003
    Co-Authors: Jean-marc Nabholtz, A Buzdar, John F.r. Robertson, J Bonneterre, B Thurlimann
    Abstract:

    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.

  • Anastrozole in the management of breast cancer.
    Expert opinion on pharmacotherapy, 2002
    Co-Authors: Jean-marc Nabholtz, David M. Reese
    Abstract:

    Anastrozole (Arimidex, AstraZeneca) is a third-generation aromatase inhibitor which rapidly reduces oestradiol concentrations to below detectable levels. It is both potent and selective for the aromatase enzyme, with near-maximal suppression of serum oestrogens occurring at the clinical dose of 1 mg/day in postmenopausal women with advanced breast cancer. Anastrozole has also been shown to be a potent suppressor of intratumoural oestrogens, with responses comparable to those in serum. The results of two large, identically designed, randomised trials in postmenopausal women with advanced breast cancer who had progressed on tamoxifen showed that oral Anastrozole 1 mg/day produced a statistically significant survival advantage over megestrol acetate 40 mg q.i.d. The median duration of survival was 26.7 months for Anastrozole versus 22.5 months for megestrol acetate. Anastrozole was as well-tolerated as megestrol acetate, while weight gain was significantly increased in the megestrol acetate group compared with the Anastrozole group. In another Phase III clinical trial involving 1021 postmenopausal women with advanced breast cancer, Anastrozole showed a statistically significant advantage over tamoxifen in median time to progression in a combined analysis of 611 patients who were known to be oestrogen receptor- or progesterone receptor-positive. Anastrozole was as well-tolerated as tamoxifen, with a low rate of withdrawals (2%) due to drug-related adverse events. In addition, Anastrozole was associated with fewer thromboembolic events and episodes of vaginal bleeding than tamoxifen. For women with hormone receptor-positive tumours who progress on tamoxifen, Anastrozole is superior to megestrol acetate. In addition, Anastrozole is a reasonable alternative to tamoxifen for first-line endocrine therapy of advanced breast cancer. Recent data confirm an emerging role for Anastrozole as adjuvant therapy for primary breast cancer in postmenopausal patients. Anastrozole is also being investigated in the neoadjuvant setting.

Anthony Howell - One of the best experts on this subject based on the ideXlab platform.

  • effect of Anastrozole and tamoxifen as adjuvant treatment for early stage breast cancer 10 year analysis of the atac trial
    Lancet Oncology, 2010
    Co-Authors: Jack Cuzick, Ivana Sestak, A Buzdar, M Baum, Anthony Howell, Mitch Dowsett, John F. Forbes
    Abstract:

    Summary Background The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of Anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months. Methods We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (Anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (Anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: Anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. Findings Patients were followed up for a median of 120 months (range 0–145); there were 24 522 woman-years of follow-up in the Anastrozole group and 23 950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the Anastrozole group compared with the tamoxifen group for disease-free survival (hazard ratio [HR] 0·91, 95% CI 0·83–0·99; p=0·04), time to recurrence (0·84, 0·75–0·93; p=0·001), and time to distant recurrence (0·87, 0·77–0·99; p=0·03). For hormone-receptor-positive patients, the results were also significantly in favour of the Anastrozole group for disease-free survival (HR 0·86, 95% CI 0·78–0·95; p=0·003), time to recurrence (0·79, 0·70–0·89; p=0·0002), and time to distant recurrence (0·85, 0·73–0·98; p=0·02). In hormone-receptor-positive patients, absolute differences in time to recurrence between Anastrozole and tamoxifen increased over time (2·7% at 5 years and 4·3% at 10 years) and recurrence rates remained significantly lower on Anastrozole than tamoxifen after treatment completion (HR 0·81, 95% CI 0·67–0·98; p=0·03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with Anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0·87, 95% CI 0·74–1·02; p=0·09), but there was little difference in overall mortality (0·95, 95% CI 0·84–1·06; p=0·4). Fractures were more frequent during active treatment in patients receiving Anastrozole than those receiving tamoxifen (451 vs 351; OR 1·33, 95% CI 1·15–1·55; p vs 112; OR 0·98, 95% CI 0·74–1·30; p=0·9). Treatment-related serious adverse events were less common in the Anastrozole group than the tamoxifen group (223 Anastrozole vs 369 tamoxifen; OR 0·57, 95% CI 0·48–0·69; p vs 78; OR 0·84, 95% CI 0·60–1·19; p=0·3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with Anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported. Interpretation These data confirm the long-term superior efficacy and safety of Anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer. Funding AstraZeneca.

  • Undesirable Gynaecological and Operative Interventions during Treatment of Breast Cancer with Anastrozole and Tamoxifen
    Geburtshilfe Und Frauenheilkunde, 2010
    Co-Authors: W Distler, Jack Cuzick, Anthony Howell, Sean Duffy, U. Canzler, Michael J. Baum
    Abstract:

    AIM: This study was performed to investigate whether the data of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial provides evidence that treatment with Anastrozole results in a lower incidence of gynaecological adverse events (AE) than tamoxifen. MATERIALS AND METHODS: In 6186 postmenopausal patients receiving Anastrozole or tamoxifen in the main ATAC trial and in those 4465 women who had an intact uterus at the baseline time of the study, a retrospective analysis of all gynaecological AEs and interventions was conducted. RESULTS: Patients treated with tamoxifen experienced significantly more gynaecological AEs than those taking Anastrozole (34.2 vs 20.5 %; p < 0.0001). This led to more diagnostic and/or therapeutic interventions, including an almost 4-fold increase in the hysterectomy rate (5.1 vs. 1.3 %; p < 0.0001). The majority of gynaecological AEs with tamoxifen occurred during the first 2.5 years of treatment. CONCLUSION: The lower incidence of gynaecological adverse events and interventions with Anastrozole and the early occurrence of AEs offer further support for the use of Anastrozole as the initial adjuvant treatment in postmenopausal patients with early hormone receptor-positive breast cancer. However, the oncological parameters and the side-effect profile of Anastrozole need to be considered in the individual patient.

  • a lower incidence of gynecologic adverse events and interventions with Anastrozole than with tamoxifen in the atac trial
    American Journal of Obstetrics and Gynecology, 2009
    Co-Authors: Sean Duffy, Jack Cuzick, Anthony Howell, W Distler, Michael Baum
    Abstract:

    Objective Results of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial have shown that tamoxifen is associated with a significantly higher incidence of gynecologic adverse events than Anastrozole. Study Design This was a retrospective analysis of all gynecologic adverse events and interventions conducted in patients receiving Anastrozole or tamoxifen in the main ATAC trial database. Results Women taking tamoxifen experienced significantly more gynecologic adverse events than those taking Anastrozole (34.2% vs 20.5%; P P Conclusion The lower incidence of gynecologic adverse events and interventions with Anastrozole and the early occurrence of these events provide further support for using Anastrozole as the initial adjuvant treatment for early hormone receptor–positive breast cancer.

  • Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early stage breast cancer results of the atac arimidex tamoxifen alone or in combination trial efficacy and safety update an
    Cancer, 2003
    Co-Authors: Michael Baum, A Buzdar, Jack Cuzick, Anthony Howell, J Forbes, J Houghton, Tarek Sahmoud
    Abstract:

    BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, Anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving Anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by Anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving Anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor Anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the Anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of Anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, Anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, Anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of Anastrozole are likely to be maintained in the long term and provide further support for the status of Anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer. Copyright 2003 American Cancer Society.

  • fulvestrant versus Anastrozole for the treatment of advanced breast carcinoma in postmenopausal women a prospective combined analysis of two multicenter trials
    Cancer, 2003
    Co-Authors: John F.r. Robertson, L Mauriac, Anthony Howell, Kent C Osborne, S Jones, Matthew J Ellis, Ulrich R Kleeberg, Steven E Come, Ignace Vergote, Stan Gertler
    Abstract:

    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, ≈ 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. Cancer 2003;98:229–38. © 2003 American Cancer Society.