Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study.

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Abstract

To test whether combining bevacizumab, an anti-vascular endothelial growth factor treatment, with endocrine therapy (ET) could potentially delay the emergence of resistance to ET.

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Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.

Stephen Johnston, John Pippen, Xavier Pivot … (2009)

Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

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Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial.

Rowan Chlebowski, Susan L Hendrix, Robert D. Langer … (2003)

The Women's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography. To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations. Following a comprehensive breast cancer risk assessment, 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter. Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure. In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P =.003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P =.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P =.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration. Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.

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Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.

Bella Kaufman, John Mackey, Michael Clemens … (2009)

TAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor-copositive metastatic breast cancer (MBC). Postmenopausal women with HER2/hormone receptor-copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Results Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor-positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure. Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.

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Author and article information

Journal

Journal ID (iso-abbrev): J. Clin. Oncol.

Title: Journal of clinical oncology : official journal of the American Society of Clinical Oncology

ISSN (Electronic): 1527-7755

ISSN (Print): 0732-183X

Publication date (Electronic): Mar 20 2015

Volume: 33

Issue: 9

Affiliations

[1 ] Miguel Martín, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense; Noelia Martinez, University Hospital Ramón y Cajal; José Ángel Garcia-Saenz, University Hospital Clínico San Carlos; Eva Carrasco, Grupo Español de Investigación en Cáncer de Mama, Madrid; Serafín Morales, Hospital Arnau de Vilanova de Lérida, Lérida; Angel Guerrero, Valencian Institute of Oncology, Valencia; Antonio Anton, University Hospital Miguel Servet, Zaragoza; Montserrat Muñoz, University Hospital Clinic i Provincial; Mireia Margeli, Hospital Universitario Germans Trias i Pujol, Barcelona; Miguel Gil, Catalan Institute of Oncology, Hospitalet; Manuel Ramos, Centro Oncológico de Galicia, La Coruña; Juan R. De la Haba-Rodriguez, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) -Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain; Sibylle Loibl, Gunter von Minckwitz, and Keyur Mehta, German Breast Group, Neu-Isenburg; Sibylle Loibl, Gunter von Minckwitz, and Keyur Mehta, Sana Klinikum Offenbach, Offenbach; Bahriye Aktas, University Women's Hospital Essen, Essen; Winfried Schoenegg, Medical Practice Berlin, Berlin; Cornelia Liedtke, University Women's Hospital Münster, Münster; Cornelia Liedtke, University Hospital Lübeck, Lübeck; and Grischa Wachsmann, Klinikum Böblingen, Böblingen, Germany. mmartin@geicam.org.

[2 ] Miguel Martín, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense; Noelia Martinez, University Hospital Ramón y Cajal; José Ángel Garcia-Saenz, University Hospital Clínico San Carlos; Eva Carrasco, Grupo Español de Investigación en Cáncer de Mama, Madrid; Serafín Morales, Hospital Arnau de Vilanova de Lérida, Lérida; Angel Guerrero, Valencian Institute of Oncology, Valencia; Antonio Anton, University Hospital Miguel Servet, Zaragoza; Montserrat Muñoz, University Hospital Clinic i Provincial; Mireia Margeli, Hospital Universitario Germans Trias i Pujol, Barcelona; Miguel Gil, Catalan Institute of Oncology, Hospitalet; Manuel Ramos, Centro Oncológico de Galicia, La Coruña; Juan R. De la Haba-Rodriguez, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) -Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain; Sibylle Loibl, Gunter von Minckwitz, and Keyur Mehta, German Breast Group, Neu-Isenburg; Sibylle Loibl, Gunter von Minckwitz, and Keyur Mehta, Sana Klinikum Offenbach, Offenbach; Bahriye Aktas, University Women's Hospital Essen, Essen; Winfried Schoenegg, Medical Practice Berlin, Berlin; Cornelia Liedtke, University Women's Hospital Münster, Münster; Cornelia Liedtke, University Hospital Lübeck, Lübeck; and Grischa Wachsmann, Klinikum Böblingen, Böblingen, Germany.

Article

Publisher Item ID: JCO.2014.57.2388

DOI: 10.1200/JCO.2014.57.2388

PubMed ID: 25691671

SO-VID: e9eb4518-76a1-4d06-a96c-3e95495f4712

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Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study.

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Model Reduction of Parametrized Systems 2015

Most cited references 16

Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.

Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial.

Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.

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