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Ian E. Smith - One of the best experts on this subject based on the ideXlab platform.
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comparative efficacy and safety of adjuvant Letrozole versus anastrozole in postmenopausal patients with hormone receptor positive node positive early breast cancer final results of the randomized phase iii femara versus anastrozole clinical evaluati
Journal of Clinical Oncology, 2017Co-Authors: Ian E. Smith, Bent Ejlertsen, Denise A Yardley, Howard A Burris, Richard De Boer, Dino Amadori, Kristi Mcintyre, Michael Gnant, W Jonat, Kathleen I PritchardAbstract:PurposeThe Letrozole (Femara) Versus Anastrozole Clinical Evaluation (FACE) study compared the efficacy and safety of adjuvant Letrozole versus anastrozole in postmenopausal patients with hormone receptor (HR) –positive and node-positive early breast cancer (eBC).MethodsPostmenopausal women with HR-positive and node-positive eBC were randomly assigned to receive adjuvant therapy with either Letrozole (2.5 mg) or anastrozole (1 mg) once per day for 5 years or until recurrence of disease. Patients were stratified on the basis of the number of lymph nodes and human epidermal growth factor receptor 2 status. The primary end point was 5-year disease-free survival (DFS), and the key secondary end points were overall survival and safety.ResultsA total of 4,136 patients were randomly assigned to receive either Letrozole (n = 2,061) or anastrozole (n = 2,075). The final analysis was done at 709 DFS events (Letrozole, 341 [16.5%]; anastrozole, 368 [17.7%]). The 5-year estimated DFS rate was 84.9% for Letrozole vers...
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assessment of Letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor positive breast cancer the big 1 98 randomised clinical trial at 8 1 years median follow up
Lancet Oncology, 2011Co-Authors: Meredith M. Regan, Aron Goldhirsch, Ian E. Smith, Louis Mauriac, John F. Forbes, P Neven, Anita Giobbiehurder, Bent Ejlertsen, Istvan Lang, Andrew M WardleyAbstract:Summary Background Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. Methods BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or Letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or Letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for Letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to Letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to Letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to Letrozole monotherapy included patients enrolled and randomly assigned to Letrozole for 5 years, Letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by Letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.gov NCT00004205. Findings 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0–12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with Letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to Letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to Letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by Letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0–12·4), Letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74–0·92], overall survival HR 0·79 [0·69–0·90], DRFI HR 0·79 [0·68–0·92], BCFI HR 0·80 [0·70–0·92]; intention-to-treat disease-free survival HR 0·86 [0·78–0·96], overall survival HR 0·87 [0·77–0·999], DRFI HR 0·86 [0·74–0·998], BCFI HR 0·86 [0·76–0·98]). At a median follow-up of 8·0 years from randomisation (range 0–11·2) for the comparison of the sequential groups with Letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for Letrozole monotherapy, Letrozole followed by tamoxifen, and tamoxifen followed by Letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. Interpretation For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by Letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and Letrozole do not improve outcome compared with Letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. Funding Novartis, United States National Cancer Institute, International Breast Cancer Study Group.
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Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer.
The New England journal of medicine, 2009Co-Authors: Henning T. Mouridsen, Anita Giobbie-hurder, Aron Goldhirsch, Beat Thürlimann, Robert Paridaens, Ian E. Smith, Louis Mauriac, John F. Forbes, Karen N. Price, Meredith M. ReganAbstract:BACKGROUND: The aromatase inhibitor Letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and Letrozole is superior to Letrozole therapy alone. METHODS: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of Letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment with the other. We compared the sequential treatments with Letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of Letrozole versus tamoxifen monotherapy in 4922 women. RESULTS: At a median follow-up of 71 months after randomization, disease-free survival was not significantly improved with either sequential treatment as compared with Letrozole alone (hazard ratio for tamoxifen followed by Letrozole, 1.05; 99% confidence interval [CI], 0.84 to 1.32; hazard ratio for Letrozole followed by tamoxifen, 0.96; 99% CI, 0.76 to 1.21). There were more early relapses among women who were assigned to tamoxifen followed by Letrozole than among those who were assigned to Letrozole alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with Letrozole and those assigned to treatment with tamoxifen (hazard ratio for Letrozole, 0.87; 95% CI, 0.75 to 1.02; P=0.08). The rate of adverse events was as expected on the basis of previous reports of Letrozole and tamoxifen therapy. CONCLUSIONS: Among postmenopausal women with endocrine-responsive breast cancer, sequential treatment with Letrozole and tamoxifen, as compared with Letrozole monotherapy, did not improve disease-free survival. The difference in overall survival with Letrozole monotherapy and tamoxifen monotherapy was not statistically significant. (ClinicalTrials.gov number, NCT00004205.)
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Letrozole versus tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy
The Journal of Steroid Biochemistry and Molecular Biology, 2003Co-Authors: Ian E. SmithAbstract:Letrozole versus tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy. Letrozole, a third generation aromatase inhibitor, has been compared with tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy. In a first-line trial in advanced disease, 939 post menopausal women were randomised double blind to receive treatment with Letrozole 2.5 mg daily or tamoxifen 20 mg daily. Letrozole was significantly superior in terms of median time to progression (9.4 months versus 6.1 months, P = 0.0001), objective response (30% versus 20%, P = 0.0006), and clinical benefit (49% versus 38%, P = 0.0001). Superiority of Letrozole was independent of disease site, receptor status, or prior adjuvant anti-oestrogen therapy. In an extended phase of this trial, 200 patients were crossed over to tamoxifen after Letrozole, compared with 197 crossed over to Letrozole after tamoxifen. Median overall survival was 34 months for Letrozole versus 30 months for tamoxifen (not significant). In a similar randomised double-blind neoadjuvant trial, 337 post menopausal patients with large ER/or PgR positive T2-T4 cancers, either requiring mastectomy or locally advanced, were randomised to preoperative Letrozole or tamoxifen for 4 months prior to surgery. Overall response was 55% for Letrozole versus 36% for tamoxifen (P < 0.001). Conservative surgery was possible in 45% of patients treated with Letrozole versus 35% with tamoxifen (P = 0.022). In both trials, both treatments were well tolerated with no significant differences in side effects. These results indicate that Letrozole is more active than tamoxifen both as neoadjuvant therapy and as first-line treatment in advanced disease. They support the importance of current adjuvant trials comparing the two treatments. (C) 2003 Elsevier Ltd. All rights reserved.
Kathleen I Pritchard - One of the best experts on this subject based on the ideXlab platform.
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comparative efficacy and safety of adjuvant Letrozole versus anastrozole in postmenopausal patients with hormone receptor positive node positive early breast cancer final results of the randomized phase iii femara versus anastrozole clinical evaluati
Journal of Clinical Oncology, 2017Co-Authors: Ian E. Smith, Bent Ejlertsen, Denise A Yardley, Howard A Burris, Richard De Boer, Dino Amadori, Kristi Mcintyre, Michael Gnant, W Jonat, Kathleen I PritchardAbstract:PurposeThe Letrozole (Femara) Versus Anastrozole Clinical Evaluation (FACE) study compared the efficacy and safety of adjuvant Letrozole versus anastrozole in postmenopausal patients with hormone receptor (HR) –positive and node-positive early breast cancer (eBC).MethodsPostmenopausal women with HR-positive and node-positive eBC were randomly assigned to receive adjuvant therapy with either Letrozole (2.5 mg) or anastrozole (1 mg) once per day for 5 years or until recurrence of disease. Patients were stratified on the basis of the number of lymph nodes and human epidermal growth factor receptor 2 status. The primary end point was 5-year disease-free survival (DFS), and the key secondary end points were overall survival and safety.ResultsA total of 4,136 patients were randomly assigned to receive either Letrozole (n = 2,061) or anastrozole (n = 2,075). The final analysis was done at 709 DFS events (Letrozole, 341 [16.5%]; anastrozole, 368 [17.7%]). The 5-year estimated DFS rate was 84.9% for Letrozole vers...
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intent to treat analysis of the placebo controlled trial of Letrozole for extended adjuvant therapy in early breast cancer ncic ctg ma 17
Annals of Oncology, 2008Co-Authors: James N Ingle, Joseph L Pater, Hyman B Muss, Silvana Martino, Nicholas J Robert, Martine Piccart, Monica Castiglione, Lois E Shepherd, Kathleen I Pritchard, Robert B LivingstonAbstract:contralateral breast cancers (CLBCs) (164 Letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (Letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55–0.83, P = 0.0001] and showed superiority for Letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62–1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for Letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39–0.97, P = 0.033). Conclusions: Patients originally randomly assigned to receive Letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking Letrozole after unblinding.
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a randomized trial of Letrozole in postmenopausal women after five years of tamoxifen therapy for early stage breast cancer
Obstetrical & Gynecological Survey, 2004Co-Authors: Paul E Goss, James N Ingle, Hyman B Muss, Silvana Martino, Nicholas J Robert, Martine Piccart, Lois E Shepherd, M Castiglione, Dongsheng Tu, Kathleen I PritchardAbstract:Tamoxifen, given for 5 years after surgery for hormone-dependent breast cancer, prolongs disease-free survival and overall survival. No added effect is noted with more than 5 years of treatment. This study, enrolling postmenopausal women who had been treated for early-stage breast cancer, was intended to show whether Letrozole improves the outcome after tamoxifen therapy is withdrawn. Letrozole is an aromatase inhibitor that suppresses estrogen production. Using a randomized, double-blind design, 5187 women who had taken adjuvant tamoxifen therapy for 4.5 to 6 years were assigned to receive 2.5 mg Letrozole or placebo orally each day for 5 years. All participants were age 50 and older when tamoxifen therapy began, and all had a tumor that was positive for estrogen receptors and/or progesterone receptors. After a median follow up of 2.4 years, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the other breast, 75 in the Letrozole-treated group and 132 in placebo recipients. The estimated 4-year disease-free survival rates were 93% and 87%, respectively. The hazard ratio for cancer in the Letrozole group was 0.57. Women with negative lymph nodes did at least as well as those with node-positive disease when given Letrozole. Overall survival rates were 96% in the Letrozole group and 94% in placebo patients, with a hazard ratio in the former group of 0.76. Hot flashes, arthritislarthralgia, and myalgia were more frequent in the Letrozole group, but vaginal bleeding occurred more often in the placebo group. Comparable numbers of patients (4.5% and 3.6%, respectively) discontinued treatment because of toxic effects. A trend was noted toward more frequent newly diagnosed osteoporosis in patients given Letrozole. The investigators concluded that Letrozole should be considered for postmenopausal women with hormone receptor-positive breast cancer who have completed 5 years of tamoxifen therapy. The optimal duration of Letrozole treatment remains to be determined.
Togas Tulandi - One of the best experts on this subject based on the ideXlab platform.
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congenital malformations among 911 newborns conceived after infertility treatment with Letrozole or clomiphene citrate
Fertility and Sterility, 2006Co-Authors: Togas Tulandi, James S B Martin, Raedah Alfadhli, Nadia Kabli, Rachel Forman, Jason Hitkari, Clifford L Librach, Ellen Greenblatt, Robert F CasperAbstract:Objective To evaluate the incidence of congenital malformations among offspring of mothers who conceived with clomiphene citrate (CC) or with Letrozole treatment for infertility. Design Retrospective study. Setting 5 fertility centers in Canada. Patients 911 newborns from women who conceived following CC or Letrozole treatment. Interventions Examination of medical files of both mother and newborn, and cross-checked with the parents by telephone calls. Main Outcome Measures Identified major and minor congenital malformations, birth weight, age of the mother, and type of treatment that led to the conception. Results Overall, congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the Letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%). The major malformation rate in the Letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397). One newborn in the Letrozole group was found to have a ventricular septal defect (0.2%) compared to 4 newborns in the CC group (1.0%). In addition, the rate of all congenital cardiac anomalies was significantly higher (P: 0.02) in the CC group (1.8%) compared to the Letrozole group (0.2%). Conclusion There was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after Letrozole or CC treatments. However, it appears that congenital cardiac anomaly is less frequent in the Letrozole group. The concern that Letrozole use for ovulation induction could be teratogenic is unfounded based on our data.
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A randomized trial of superovulation with two different doses of Letrozole
Fertility and sterility, 2006Co-Authors: Raedah Al-fadhli, Camille Sylvestre, William Buckett, Seang Lin Tan, Togas TulandiAbstract:Objective The aim of this study was to evaluate the effects of either a 2.5-mg or a 5-mg daily dose of Letrozole in women undergoing superovulation and intrauterine insemination (IUI). Design Prospective randomized trial. Setting Academic teaching hospital. Patient(s) Women 1 year in duration. Intervention(s) Patients were randomized into either a 2.5-mg dose of Letrozole (34 patients) or a 5-mg dose of Letrozole (38 patients) daily for 5 days. When the leading follicle reached 18 mm in diameter, ovulation was triggered by an injection of hCG and IUI was performed 24 and 48 hours later. Main Outcome Measure(s) The number of follicles, endometrial thickness, and pregnancy rate. Result(s) Compared with those treated with 2.5 mg of Letrozole, the total number of follicles was significantly higher in patients receiving 5 mg of Letrozole. No difference in the endometrial thickness was found between the two groups. The pregnancy rate per cycle in patients receiving 5mg of Letrozole was statistically higher than in patients receiving 2.5 mg of Letrozole (26.3% vs. 5.9%, P Conclusion(s) Compared with the daily dose of 2.5 mg, 5 mg of Letrozole is associated with more follicles and a higher pregnancy rate. It appears that 5 mg daily for 5 days is a preferable Letrozole dose for superovulation.
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a randomized trial of Letrozole versus clomiphene citrate in women undergoing superovulation
Fertility and Sterility, 2004Co-Authors: Haya Alfozan, Seang Lin Tan, Maha Alkhadouri, Togas TulandiAbstract:Objective To compare the effects of the aromatase inhibitor Letrozole (7.5 mg) and clomiphene citrate (CC; 100 mg) in women undergoing superovulation and IUI. Design Prospective randomized trial. Setting University teaching hospital. Patient(s) We studied a total of 238 cycles of superovulation and IUI in women with idiopathic infertility. Interventions Patients were randomized into treatment with 7.5 mg of Letrozole daily (74 patients, 115 cycles) or 100 mg of CC daily (80 patients, 123 cycles). Main outcome measure(s) Number of follicles, endometrial thickness, pregnancy rate, and miscarriage rate. Result(s) The mean age, parity, and duration of infertility in both groups of patients were similar. There was no significant difference between the total number of developing follicles in the Letrozole (5.7 ± 3.7) and in the CC groups (4.8 ± 2.5). The number of follicles of ≥14 mm and of >18 mm were 2.1 ± 1.2 and 1.4 ± 0.7 in the Letrozole group, and 1.7 ± 0.9 and 1.1 ± 0.5 in the CC group, respectively. No difference was found in the endometrial thickness between the two groups (7.1 ± 0.2 mm in the Letrozole group, 8.2 ± 5.9 mm in the CC group). The pregnancy rate per cycle was 11.5 % in the Letrozole group and 8.9 % in the CC group. Four of the 11 pregnancies in the CC group resulted in a miscarriage (36.6 % ). Conclusion(s) Superovulation and IUI with Letrozole and CC are associated with similar pregnancy rates, but the miscarriage rate is higher with CC. The ideal dose of Letrozole remains unknown and further study is needed.
Angela Brodie - One of the best experts on this subject based on the ideXlab platform.
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seribantumab an anti erbb3 antibody delays the onset of resistance and restores sensitivity to Letrozole in an estrogen receptor positive breast cancer model
Molecular Cancer Therapeutics, 2015Co-Authors: Michael D Curley, Bambang Adiwijaya, Gauri Sabnis, Lucia Wille, Gabriela Garcia, Angela Brodie, Armina A Kazi, Victor Moyo, Gavin MacbeathAbstract:Heregulin-driven ERBB3 signaling has been implicated as a mechanism of resistance to cytotoxic and antiendocrine therapies in preclinical breast cancer models. In this study, we evaluated the effects of seribantumab (MM-121), a heregulin-blocking anti-ERBB3 monoclonal antibody, alone and in combination with the aromatase inhibitor Letrozole, on cell signaling and tumor growth in a preclinical model of postmenopausal estrogen receptor–positive (ER+) breast cancer. In vitro , heregulin treatment induced estrogen receptor phosphorylation in MCF-7Ca cells, and long-term Letrozole-treated (LTLT-Ca) cells had increased expression and activation levels of EGFR, HER2, and ERBB3. Treatment with seribantumab, but not Letrozole, inhibited basal and heregulin-mediated ERBB receptor phosphorylation and downstream effector activation in Letrozole-sensitive (MCF-7Ca) and -refractory (LTLT-Ca) cells. Notably, in MCF-7Ca–derived xenograft tumors, cotreatment with seribantumab and Letrozole had increased antitumor activity compared with Letrozole alone, which was accompanied by downregulated PI3K/MTOR signaling both prior to and after the development of resistance to Letrozole. Moreover, the addition of an MTOR inhibitor to this treatment regimen did not improve antitumor activity and was not well tolerated. Our results demonstrate that heregulin-driven ERBB3 signaling mediates resistance to Letrozole in a preclinical model of ER+ breast cancer, suggesting that heregulin-expressing ER+ breast cancer patients may benefit from the addition of seribantumab to antiendocrine therapy. Mol Cancer Ther; 14(11); 2642–52. ©2015 AACR . This article is featured in Highlights of This Issue, [p. 2409][1] [1]: /lookup/volpage/14/2409?iss=11
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seribantumab an anti erbb3 antibody delays theonsetofresistanceandrestoressensitivityto Letrozoleinanestrogenreceptor positivebreast
2015Co-Authors: Michael D Curley, Bambang Adiwijaya, Gauri Sabnis, Lucia Wille, Gabriela Garcia, Armina Kazi, Angela Brodie, Victor Moyo, Gavin MacbeathAbstract:Heregulin-driven ERBB3 signaling has been implicated as a mechanism of resistance to cytotoxic and antiendocrine therapies in preclinical breast cancer models. In this study, we evaluated the effects of seribantumab (MM-121), a heregulinblocking anti-ERBB3 monoclonal antibody, alone and in combination with the aromatase inhibitor Letrozole, on cell signaling and tumor growth in a preclinical model of postmenopausal estrogen receptor–positive (ER þ ) breast cancer. In vitro, heregulin treatment induced estrogen receptor phosphorylation in MCF-7Ca cells, and long-term Letrozole-treated (LTLT-Ca) cells had increased expression and activation levels of EGFR, HER2, and ERBB3. Treatment with seribantumab, but not Letrozole, inhibited basal and heregulin-mediated ERBB receptor phosphorylation and downstream effector activation in Letrozole-sensitive (MCF-7Ca) and -refractory (LTLT-Ca) cells. Notably, in MCF-7Ca–derived xenograft tumors, cotreatment with seribantumab and Letrozole had increased antitumor activity compared with Letrozole alone, which was accompanied by downregulated PI3K/MTOR signaling both prior to and after the development of resistance to Letrozole. Moreover, the addition of an MTOR inhibitor to this treatment regimen did not improve antitumor activity and was not well tolerated. Our results demonstrate that heregulin-driven ERBB3 signaling mediates resistance to Letrozole in a preclinical model of ER þ breast cancer, suggesting that heregulin-expressing ER þ breast cancer patients may benefit from the addition of seribantumab to antiendocrine therapy.Mol Cancer Ther; 14(11);
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Sensitivity to the Aromatase Inhibitor Letrozole Is Prolonged After a “Break” in Treatment
Molecular cancer therapeutics, 2010Co-Authors: Gauri Sabnis, Luciana Macedo, Olga Goloubeva, Rabia A. Gilani, Angela BrodieAbstract:Using a hormone-dependent xenograft model, we established that loss of response to Letrozole was accompanied by upregulation of the Her-2/mitogen-activated protein kinase (MAPK) pathway and downregulation of estrogen receptor alpha (ERalpha) and aromatase activity. In our previous study, we showed that stopping Letrozole treatment or adding trastuzumab could reverse acquired resistance. In this study, we compared the effects of intermittent Letrozole treatment and switching treatment between Letrozole and trastuzumab on tumor growth in an attempt to optimize discontinuous Letrozole treatment. The mice were treated with Letrozole until the tumors developed resistance and then were divided into three groups: (a) Letrozole, (b) trastuzumab, and (c) "off" (Delta(4)A supplement only); tumors were collected every week to examine changes in tumor protein expression and activity. In off group tumors, Her-2/p-MAPK activation gradually decreased and ERalpha and aromatase protein (and activity) increased. Within the first week of trastuzumab treatment, Her-2 and MAPK were downregulated and ERalpha was upregulated. When Letrozole-resistant MCF-7Ca tumors were taken off treatment for 4 weeks, the second course of Letrozole treatment provided a much longer duration of response (P = 0.02). However, switching treatment to trastuzumab for 4 weeks did not provide any inhibition of tumor growth. Our studies revealed that the adaptation of cells to a low-estrogen environment by upregulation of Her-2/MAPK and downregulation of ERalpha/aromatase was reversed on Letrozole withdrawal. The tumors once again became responsive to Letrozole for a significant period. These results suggest that response to Letrozole can be prolonged by a short "break" in the treatment.
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additive antitumor effect of aromatase inhibitor Letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model
Cancer Research, 2005Co-Authors: Danijela Jelovac, Olga Goloubeva, Luciana Macedo, Venkatesh D Handratta, Angela BrodieAbstract:Blocking estrogen receptors with antiestrogens and blocking estrogen synthesis with aromatase inhibitors are two strategies currently being used for reducing the effect of estrogen in postmenopausal estrogen receptor-positive breast cancer patients. To optimize these treatment strategies, we have investigated whether tumor progression can be delayed by combining the pure antiestrogen fulvestrant with the nonsteroidal aromatase inhibitor Letrozole. These studies were done in ovariectomized, athymic mice bearing tumors of estrogen receptor-positive human breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). Groups of mice with equivalent tumor volumes were injected s.c. daily with vehicle (control; n = 6), fulvestrant (1 mg/d; n = 7), Letrozole (10 microg/d; n = 18), or Letrozole (10 microg/d) plus fulvestrant (1 mg/d; n = 5). All treatments were effective in suppressing tumor growth compared with controls (P < 0.001). Tumor volumes of the fulvestrant-treated group had doubled in 10 weeks. After 19 weeks of Letrozole (10 microg/d) treatment when tumors had nearly doubled in volume, mice (n = 18) were assigned to second-line therapy with Letrozole (100 microg/d; n = 6), tamoxifen (100 microg/d; n = 6), or remained on Letrozole treatment (10 microg/d; n = 6). However, tumors continued to increase in volume in these groups. Tumors of animals treated with the combination of Letrozole plus Faslodex regressed over 29 weeks of treatment by 45%. Thus, the combination of Letrozole plus fulvestrant was more effective in suppressing tumor growth than either Letrozole or fulvestrant alone or sequential therapies with tamoxifen or a higher dose of Letrozole (100 microg/d).
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Model systems: mechanisms involved in the loss of sensitivity to Letrozole.
The Journal of Steroid Biochemistry and Molecular Biology, 2005Co-Authors: Angela Brodie, Gauri Sabnis, Luciana Macedo, Danijela Jelovac, Brian J. Long, Olga GoloubevaAbstract:Abstract A number of models have been used to study the development and treatment of breast cancer. Since most breast cancer patients are postmenopausal and treated with hormone therapy, we developed a model to simulate this type of patient. Tumors of human estrogen receptor (ER)—positive breast cancer cells transfected with aromatase (MCF-7Ca) are grown in immune suppressed mice. In this model, we have explored a number of strategies to optimize the antitumor efficacy of treatment such as combining the non-steroidal aromatase inhibitor Letrozole with the antiestrogens, tamoxifen. This combination resulted in tumor suppression similar to the antiestrogen alone, but was less effective than Letrozole alone. Clinical findings with the non-steroidal inhibitor anastrozole in combination with tamoxifen (ATAC trial) were consistent with our results. Although Letrozole was the most effective single agent tested in the model, tumors ultimately began to grow during continued treatment. To investigate the mechanisms by which tumors adapt to growth during Letrozole treatment, we determined the expression of signaling proteins in tumors during the course of Letrozole treatment compared to the tumors of control mice. We found that tumors initially up regulated the ER, but subsequently receptor levels decreased in tumors unresponsive to Letrozole. Adapter proteins (p-Shc and Grb-2) as well as all of the signaling proteins in the MAPK cascade (p-Raf, p-Mek1/2, and p-MAPK), but not Akt, were increased in tumors no longer responsive to Letrozole. The results suggest that tumor cells adapt to estrogen deprivation during Letrozole treatment by activation of alternate signaling pathways to increase transcription. When Letrozole was combined with the pure antiestrogen fulvestrant, to down regulate ER, the combination was more effective than either Letrozole or fulvestrant alone. Tumors regressed by 45% and were maintained without growth for the duration of the experiment (29 weeks). Down regulation of ER by fulvestrant may prevent cross talk between these signaling pathways. The results suggest that achieving more complete estrogen blockade may delay development of hormone-independent signaling pathways regulating proliferation.
Meredith M. Regan - One of the best experts on this subject based on the ideXlab platform.
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assessment of Letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor positive breast cancer the big 1 98 randomised clinical trial at 8 1 years median follow up
Lancet Oncology, 2011Co-Authors: Meredith M. Regan, Aron Goldhirsch, Ian E. Smith, Louis Mauriac, John F. Forbes, P Neven, Anita Giobbiehurder, Bent Ejlertsen, Istvan Lang, Andrew M WardleyAbstract:Summary Background Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. Methods BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or Letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or Letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for Letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to Letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to Letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to Letrozole monotherapy included patients enrolled and randomly assigned to Letrozole for 5 years, Letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by Letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.gov NCT00004205. Findings 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0–12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with Letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to Letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to Letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by Letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0–12·4), Letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74–0·92], overall survival HR 0·79 [0·69–0·90], DRFI HR 0·79 [0·68–0·92], BCFI HR 0·80 [0·70–0·92]; intention-to-treat disease-free survival HR 0·86 [0·78–0·96], overall survival HR 0·87 [0·77–0·999], DRFI HR 0·86 [0·74–0·998], BCFI HR 0·86 [0·76–0·98]). At a median follow-up of 8·0 years from randomisation (range 0–11·2) for the comparison of the sequential groups with Letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for Letrozole monotherapy, Letrozole followed by tamoxifen, and tamoxifen followed by Letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. Interpretation For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by Letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and Letrozole do not improve outcome compared with Letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. Funding Novartis, United States National Cancer Institute, International Breast Cancer Study Group.
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Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer.
The New England journal of medicine, 2009Co-Authors: Henning T. Mouridsen, Anita Giobbie-hurder, Aron Goldhirsch, Beat Thürlimann, Robert Paridaens, Ian E. Smith, Louis Mauriac, John F. Forbes, Karen N. Price, Meredith M. ReganAbstract:BACKGROUND: The aromatase inhibitor Letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and Letrozole is superior to Letrozole therapy alone. METHODS: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of Letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment with the other. We compared the sequential treatments with Letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of Letrozole versus tamoxifen monotherapy in 4922 women. RESULTS: At a median follow-up of 71 months after randomization, disease-free survival was not significantly improved with either sequential treatment as compared with Letrozole alone (hazard ratio for tamoxifen followed by Letrozole, 1.05; 99% confidence interval [CI], 0.84 to 1.32; hazard ratio for Letrozole followed by tamoxifen, 0.96; 99% CI, 0.76 to 1.21). There were more early relapses among women who were assigned to tamoxifen followed by Letrozole than among those who were assigned to Letrozole alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with Letrozole and those assigned to treatment with tamoxifen (hazard ratio for Letrozole, 0.87; 95% CI, 0.75 to 1.02; P=0.08). The rate of adverse events was as expected on the basis of previous reports of Letrozole and tamoxifen therapy. CONCLUSIONS: Among postmenopausal women with endocrine-responsive breast cancer, sequential treatment with Letrozole and tamoxifen, as compared with Letrozole monotherapy, did not improve disease-free survival. The difference in overall survival with Letrozole monotherapy and tamoxifen monotherapy was not statistically significant. (ClinicalTrials.gov number, NCT00004205.)
