Phase III, Multicenter, Double-Blind, Randomized Study of Letrozole, an Aromatase Inhibitor, for Advanced Breast Cancer Versus Megestrol Acetate

Buzdar, Aman U.; Douma, Joeri A J; Davidson, Nancy E.; Elledge, Richard M.; Morgan, M.; Smith, Robert E.; Porter, L; Nabholtz, Jean‐Marc; Xiang, Xiao Juan; Brady, C.

doi:10.1200/jco.2001.19.14.3357

Cited by 342 publications

(148 citation statements)

References 20 publications

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“…To investigate the activities of these compounds, we have utilized a xenograft model, which we previously reported to be responsive to both antiestrogens (AEs) and aromatase inhibitors (AIs) [8]. Previous clinical trials (BIG, ATAC, MA-17) have confirmed prior results of our xenograft model [9][10][11][12][13]. As found in these studies, AIs were significantly better than AEs in controlling tumor growth.…”

Section: Introductionsupporting

confidence: 57%

Toremifene–atamestane; alone or in combination: Predictions from the preclinical intratumoral aromatase model

Sabnis

Macedo

Goloubeva

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Since most breast cancers occur in post-menopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human estrogen receptor ER positive breast cancer cells stably transfected with aromatase (Ac-1) are grown in immune compromised mice. Using this model we have explored a number of therapeutic strategies to maximize the antitumor efficacy of antiestrogens (AEs) and aromatase inhibitors (AIs). This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. In this current study we compared the effect of an AE toremifene and steroidal AI atamestane, alone or in combination, on growth of hormone dependent human breast cancer. We have also compared toremifene plus atamestane combination with tamoxifen in this study.The growth of Ac-1 cells was inhibited by tamoxifen, toremifene and atamestane in vitro with IC 50 values of 1.8±1.3μM, 1±0.3μM and 60.4±17.2μM, respectively. The combination of toremifene plus atamestane was found to be better than toremifene or atamestane alone in vitro. The effect of this combination was then studied in vivo using Ac-1 xenografts grown in ovariectomized female SCID mice. The mice were injected with toremifene (1000μg/day), atamestane (1000μg/day), tamoxifen (100μg/day), or the combination of toremifene plus atamestane. In this study, our results indicate that the combination of toremifene plus atamestane was as effective as toremifene or tamoxifen alone but may not provide any additional benefit over toremifene alone or tamoxifen alone.

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Section: Introductionsupporting

confidence: 57%

Toremifene–atamestane; alone or in combination: Predictions from the preclinical intratumoral aromatase model

Sabnis

Macedo

Goloubeva

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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“…Two similar studies with letrozole in patients in relapse with adjuvant tamoxifen or first-line antioestrogens, demonstrated that letrozole can obtain efficiency results similar or superior to megestrol acetate (Dombernowsky et al, 1998;Buzdar et al, 2001).…”

Section: Discussionmentioning

confidence: 96%

Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer

Iaffaioli¹,

Formato²,

Tortoriello³

et al. 2005

Br J Cancer

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Hormonal therapy is the preferred systemic treatment for recurrent or metastatic, post-menopausal hormone-receptor-positive breast cancer. Previous studies have shown that there is no cross-resistance between exemestane and reversible aromatase inhibitors. Exposure to hormonal therapy does not hamper later response to chemotherapy. Patients with locally advanced or metastatic, hormonal receptor positive or unknown, breast cancer were treated with oral anastrozole, until disease progression, followed by oral exemestane until new evidence of disease progression. The primary end point of the study was clinical benefit, defined as the sum of complete responses (CR), partial responses (PR) and 424 weeks stable disease (SD). In all, 100 patients were enrolled in the study. Anastrozole produced eight CR and 19 PR for an overall response rate of 27% (95% CI: 18.6 -36.8%). An additional 46 patients had long-term (424 weeks) SD for an overall clinical benefit of 73% (95% CI: 63.2 -81.4). Median time to progression (TTP) was 11 months (95% CI: 10 -12). A total of 50 patients were evaluated for the second-line treatment: exemestane produced one CR and three PR; 25 patients had SD which lasted X6 months in 18 patients. Median TTP was 5 months. Toxicity of treatment was low. Our study confirms that treatment with sequential hormonal agents can extend the period of time during which endocrine therapy can be used, thereby deferring the decision to use chemotherapy.

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“…Compared with women assigned to treatment with placebo or tamoxifen, those treated with aromatase inhibitors have consistently shown higher rates of arthralgia. In trials of women with advanced breast cancer, arthralgias have been more common in women treated with aromatase inhibitors than in the comparator group despite their lower rates of metastases, which might also cause bone pain (20)(21)(22)(23)(24).…”

Section: Evidence Linking Pharmacologically Induced Low Estrogen Levementioning

confidence: 99%

Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation

Felson¹,

Cummings²

2005

Arthritis & Rheumatism

153

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Phase III, Multicenter, Double-Blind, Randomized Study of Letrozole, an Aromatase Inhibitor, for Advanced Breast Cancer Versus Megestrol Acetate

Cited by 342 publications

References 20 publications

Toremifene–atamestane; alone or in combination: Predictions from the preclinical intratumoral aromatase model

Toremifene–atamestane; alone or in combination: Predictions from the preclinical intratumoral aromatase model

Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer

Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation

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