BIG 1–98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer

Thurlimann, B.; Keshaviah, Aparna; Mouridsen, H. T.; Mauriac, L.; Forbes, J. F.; Paridaens, Robert; Castiglione‐Gertsch, Monica; Gelber, R.D.; Smith, Ian; Goldhirsch, Aron

doi:10.1200/jco.2005.23.16_suppl.511

Cited by 79 publications

(60 citation statements)

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“…Some of the advantage of anastrozole over tamoxifen in the overall results of the ATAC trial is likely due, therefore, to the large advantage of anastrozole over tamoxifen in PRÀ cases. Although the BIG 1-98 trial (9), which compares letrozole to tamoxifen, does not support a differential outcome for PRÀ and PR+ cases for either treatment group, a differential effect of PR on prognosis and treatment benefit is entirely consistent with historical clinical experience, which suggests that PRÀ cases have a worse prognosis (10) and respond less well to tamoxifen. It is also consistent with older clinical observations (11) and more recent laboratory studies by the Osborne-Schiff laboratory (12), which suggest that loss of PR is associated with acquired tamoxifen resistance.…”

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confidence: 58%

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Is There a Role for Adjuvant Tamoxifen in Progesterone Receptor–Positive Breast Cancer? An In silico Clinical Trial

Hilsenbeck

Osborne

2006

Clinical Cancer Research

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Purpose: Subset analysis from the Arimidex, Tamoxifen, Alone or in Combination trial, a major adjuvant therapy trial, suggests that progesterone receptor^negative (PRÀ) cases may derive greater benefit from aromatase inhibitor compared with tamoxifen than PR+ cases.We postulated that estrogen receptor^positive (ER+)/PR+ patients might do as well or better by starting on tamoxifen and later switching to an aromatase inhibitor rather than by starting on an aromatase inhibitor as initial therapy. Experimental Design: We constructed a computer model using retrospective data to approximate exponential failure rates for PR+ and PRÀ in tamoxifen-treated and tamoxifen-untreated patients, adding the assumptions that about half of patients are cured at surgery and that f20% of postmenopausal ER+ early breast cancer cases are PRÀ. This model provided a very good approximation to the published overview data and to the clinical trials. We then used the failure rates to generate relapse times for a large number of cases (n = 50,000) for each treatment scenario. Results: In PRÀ cases, initial therapy with an aromatase inhibitor is superior to tamoxifen and this advantage can never be made up by switching. In PR+ cases, tamoxifen is only modestly inferior to aromatase inhibitor at the outset, and after switching to an aromatase inhibitor at 3 or 5 years the tamoxifen relapse-free survival curve catches up and then begins to surpass the aromatase inhibitor curve at 7.5 or 12 years, respectively. Discussion: Although our in silico trial is based on many assumptions, it closely approximates results of the published trials and, therefore, suggests that an in vivo comparison in ER+/PR+ patients of aromatase inhibitor versus tamoxifen followed by aromatase inhibitor may be worth considering.

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confidence: 58%

“…The outcome of interest is time to recurrence, with nonbreast cancer deaths being censored. Published data from three clinical trials and a retrospective review were used (1,3,5,6,9,14). Here, we assume all aromatase inhibitors are created equal and make no effort to attribute differential effects due to specific drugs.…”

Section: Methodsmentioning

confidence: 99%

Is There a Role for Adjuvant Tamoxifen in Progesterone Receptor–Positive Breast Cancer? An In silico Clinical Trial

Hilsenbeck

Osborne

2006

Clinical Cancer Research

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“…However, all three studies comparing AI with tamoxifen report a higher, although not significant, rate of cardiac events. For example, in the BIG 1-98 study 20 deaths due to stroke or cardiac events have been reported with letrozole as compared with 7 in the tamoxifen arm (Thurlimann et al 2005). Of course, it must be underlined that the follow-up in adjuvant trials is still too short to derive N Normanno et al: Resistance to endocrine therapy in breast cancer definitive conclusions, and that cross-trial comparisons of different AIs is not correct and should not be done.…”

Section: Adjuvant Treatmentmentioning

confidence: 99%

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Normanno

Maïo

Maio

et al. 2005

Endocr Relat Cancer

258

224

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Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogenindependent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor a (ERa) and/or increased non-genomic activity of ERa, estrogen supersensitivity, increased growth factor signaling, suppression of ERa expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

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“…Data from recent and ongoing trials of third-generation aromatase inhibitors as adjuvant therapy for postmenopausal women have challenged the position of tamoxifen by showing superior efficacy in terms of reduction of recurrence rate and a different and probably better safety profile when starting with, or switching to, an aromatase inhibitor. In some of these trials, an aromatase inhibitor has been used as initial therapy (6); in others, a switch was made to an aromatase inhibitor after several years of tamoxifen treatment (7 -12).…”

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confidence: 99%

Anastrozole as an Adjuvant Endocrine Treatment for Postmenopausal Patients with Breast Cancer: Emerging Data

Buzdar

Cuzick

2006

Clinical Cancer Research

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The Arimidex,Tamoxifen, Alone or in Combination (ATAC) trial compared the efficacy and safety of anastrozole versus tamoxifen versus the combination as initial adjuvant treatment for early breast cancer in over 9,000 postmenopausal women. Analyses at 33 and 47 months median follow-up showed that anastrozole significantly prolonged disease-free survival and time to recurrence and reduced the incidence of contralateral breast cancer compared with tamoxifen. Results of the completed treatment analysis at 68 months median follow-up confirmed the earlier findings, showing that the absolute difference in disease-free survival continued to increase beyond completion of treatment. Mature safety data from the ATAC trial show that, overall, anastrozole has a favorable safety profile compared with tamoxifen. In the absence of current data on further follow-up or the outcome of trials investigating proactive sequencing of endocrine therapies, we present a model based on several trials, including ATAC.This model suggests that using an aromatase inhibitor as initial adjuvant therapy is a better option than switching to an aromatase inhibitor after z2 years of tamoxifen. The relative toxicities of the three approved third-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, are discussed. These data suggest that long-term safety profiles may differ between aromatase inhibitors, although comprehensive comparative data for letrozole and exemestane versus tamoxifen are lacking.

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BIG 1–98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer

Cited by 79 publications

References 0 publications

Is There a Role for Adjuvant Tamoxifen in Progesterone Receptor–Positive Breast Cancer? An In silico Clinical Trial

Is There a Role for Adjuvant Tamoxifen in Progesterone Receptor–Positive Breast Cancer? An In silico Clinical Trial

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Anastrozole as an Adjuvant Endocrine Treatment for Postmenopausal Patients with Breast Cancer: Emerging Data

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