Top

Published in:

01-08-2009 | Clinical Trial

Celecoxib and exemestane versus placebo and exemestane in postmenopausal metastatic breast cancer patients: a double-blind phase III GINECO study

Authors: C. Falandry, M. Debled, T. Bachelot, T. Delozier, J. Crétin, P. Romestaing, D. Mille, B. You, L. Mauriac, E. Pujade-Lauraine, G. Freyer

Published in: Breast Cancer Research and Treatment | Issue 3/2009

Abstract

The aim of this study was to evaluate antitumor effects of cyclooxygenase-2 inhibitors in breast carcinoma and their ability to act synergistically with aromatase inhibitors (AIs). Postmenopausal metastatic breast cancer patients without previous adjuvant AI treatment received exemestane 25 mg/days plus either celecoxib 400 mg twice daily or placebo. The primary endpoint was progression-free survival (PFS). This trial was prematurely terminated (N = 157 of 342 planned) after cardiovascular toxicity was reported in other celecoxib trials. Although no PFS difference was observed between the two arms (9.8 months for both, P = 0.72), a trend favoring celecoxib was observed in 60 tamoxifen-resistant patients (9.6 vs. 5.1 months; P = 0.14) and in 126 patients treated ≥3 months before study termination (12.2 vs. 9.8 months; P = 0.09). No severe adverse events were reported. Cyclooxygenase-2 inhibitors seemingly contribute to reverse endocrine resistance in breast cancer patients, although further study is necessary to allow development of a new therapeutic strategy.

American CancerSociety (2006) Cancer facts and figures 2006. American Cancer Society, Atlanta

Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRef

Crown J, Dieras V, Kaufmann M et al (2002) Chemotherapy for metastatic breast cancer-report of a European expert panel. Lancet Oncol 3:719–727. doi:10.1016/S1470-2045(02)00927-0 PubMedCrossRef

von Minckwitz G (2006) Evidence-based treatment of metastatic breast cancer—2006 recommendations by the AGO Breast Commission. Eur J Cancer 42:2897–2908. doi:10.1016/j.ejca.2006.06.033 CrossRef

Wilcken N, Hornbuckle J, Ghersi D (2003) Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev CD002747

Beslija S, Bonneterre J, Burstein H et al (2007) Second consensus on medical treatment of metastatic breast cancer. Ann Oncol 18:215–225. doi:10.1093/annonc/mdl155 PubMedCrossRef

Bonneterre J, Buzdar A, Nabholtz JM et al (2001) Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 92:2247–2258. doi:10.1002/1097-0142(20011101)92:9<2247::AID-CNCR1570>3.0.CO;2-YPubMedCrossRef

Mouridsen H, Gershanovich M, Sun Y et al (2003) Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21:2101–2109. doi:10.1200/JCO.2003.04.194 PubMedCrossRef

Nabholtz JM, Buzdar A, Pollak M et al (2000) Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial Arimidex Study Group. J Clin Oncol 18:3758–3767PubMed

10.

Paridaens RJ, Dirix LY, Beex LV et al (2008) Results of a randomized clinical trial comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: a phase III study conducted by the EORTC Breast Cancer Cooperative Group. Breast Cancer Res Treat (in press)

11.

Schrey MP, Patel KV (1995) Prostaglandin E2 production and metabolism in human breast cancer cells and breast fibroblasts. Regulation by inflammatory mediators. Br J Cancer 72:1412–1419PubMed

12.

Huang M, Stolina M, Sharma S et al (1998) Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production. Cancer Res 58:1208–1216PubMed

13.

Chang S-H, Liu CH, Conway R et al (2004) Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci USA 101:591–596. doi:10.1073/pnas.2535911100 PubMedCrossRef

14.

Tsujii M, DuBois RN (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83:493–501. doi:10.1016/0092-8674(95)90127-2 PubMedCrossRef

15.

Tsujii M, Kawano S, Tsuji S et al (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716. doi:110.1016/S0092-8674(00)81433-6 PubMedCrossRef

16.

O’Neill GP, Ford-Hutchinson AW (1993) Expression of mRNA forcyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 330:156–160. doi:10.1016/0014-5793(93)80263-T PubMed

17.

Eberhart CE, Coffey RJ, Radhika A et al (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107:1183–1188PubMed

18.

Parrett M, Harris R, Joarder F, Clausen K, Robertson F (1997) Cyclooxygenase-2 gene expression in human breast cancer. Int J Oncol 10:503–507

19.

Liu CH, Chang S-H, Narko K et al (2001) Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276:18563–18569. doi:10.1074/jbc.M010787200 PubMedCrossRef

20.

Howe LR, Chang S-H, Tolle KC et al (2005) HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Res 65:10113–10119. doi:10.1158/0008-5472.CAN-05-1524 PubMedCrossRef

21.

Harris RE, Namboodiri KK, Farrar WB (1996) Nonsteroidal antiinflammatory drugs and breast cancer. Epidemiology 7:203–205. doi:10.1097/00001648-199603000-00017 PubMedCrossRef

22.

Kucab JE, Lee C, Chen CS et al (2005) Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumours. Breast Cancer Res 7:R796–R807. doi:10.1186/bcr1294 PubMedCrossRef

23.

Basu GD, Pathangey LB, Tinder TL et al (2004) Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer. Mol Cancer Res 2:632–642PubMed

24.

Alshafie GA, Abou-Issa HM, Seibert K, Harris RE (2000) Chemotherapeutic evaluation of celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model. Oncol Rep 7:1377–1381PubMed

25.

Howe LR, Subbaramaiah K, Patel J et al (2002) Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 62:5405–5407PubMed

26.

Lanza-Jacoby S, Miller S, Flynn J et al (2003) The cyclooxygenase-2 inhibitor, celecoxib, prevents the development of mammary tumors in HER-2/neu mice. Cancer Epidemiol Biomarkers Prev 12:1486–1491PubMed

27.

Higuchi T, Iwama T, Yoshinaga K et al (2003) A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients. Clin Cancer Res 9:4756–4760PubMed

28.

Steinbach G, Lynch PM, Phillips RKS et al (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952. doi:10.1056/NEJM200006293422603 PubMedCrossRef

29.

Muller-Decker K, Berger I, Ackermann K et al (2005) Cystic duct dilatations and proliferative epithelial lesions in mouse mammary glands upon keratin 5 promoter-driven overexpression of cyclooxygenase-2. Am J Pathol 166:575–584PubMed

30.

Pesenti E, Masferrer J, di Salle E (2001) Effect of exemestane and celecoxib alone or in combination on DBMA-induced mammary carcinoma in rats. Breast Cancer Res 69:288 abstract

31.

Canney PA, Machin MA, Curto J (2006) A feasibility study of the efficacy and tolerability of the combination of exemestane with the COX-2 inhibitor celecoxib in post-menopausal patients with advanced breast cancer. Eur J Cancer 42:2751–2756. doi:10.1016/j.ejca.2006.08.014 PubMedCrossRef

32.

Chow LW, Wong JL, Toi M (2003) Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer: preliminary report. J Steroid Biochem Mol Biol 86:443–447. doi:10.1016/S0960-0760(03)00355-8 PubMedCrossRef

33.

Dirix LY, Ignacio J, Nag S et al (2008) Treatment of advanced hormone-sensitive breast cancer in postmenopausal women with exemestane alone or in combination with celecoxib. J Clin Oncol 26:1253–1259. doi:10.1200/JCO.2007.13.3744 PubMedCrossRef

34.

Solomon SD, McMurray JJ, Pfeffer MA et al (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352:1071–1080. doi:10.1056/NEJMoa050405 PubMedCrossRef

35.

Harris R, Beebe-Donk J, Alshafie G (2006) Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer 6:27. doi:10.1186/1471-2407-6-27 PubMedCrossRef

36.

Rahme E, Ghosn J, Dasgupta K, Rajan R, Hudson M (2005) Association between frequent use of nonsteroidal anti-inflammatory drugs and breast cancer. BMC Cancer 5:159. doi:10.1186/1471-2407-5-159 PubMedCrossRef

37.

Zhao Y, Agarwal VR, Mendelson CR, Simpson ER (1996) Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. Endocrinology 137:5739–5742. doi:10.1210/en.137.12.5739 PubMedCrossRef

38.

Chow LWC, Toi M (2005) Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer. Paper presented at 28th annual San Antonio breast cancer symposium, San Antonio, 8–11 December 2005

39.

Dang CT, Dannenberg AJ, Subbaramaiah K et al (2004) Phase II study of celecoxib and trastuzumab in metastatic breast cancer patients who have progressed after prior trastuzumab-based treatments. Clin Cancer Res 10:4062–4067. doi:10.1158/1078-0432.CCR-03-0463 PubMedCrossRef

40.

US Food and Drug Administration (2004) FDA statement on the halting of a clinical trial of the Cox-2 inhibitor celebrex. US Food and Drug Administration. Available via http://www.fda.gov/bbs/topics/news/2004/NEW01144.html. Cited 24 June 2008

41.

US Food and Drug Administration (2004) Public Health Advisory: non-steroidal anti-inflammatory drug products (NSAIDs). US Food and Drug Administration. Available via http://www.fda.gov/cder/drug/advisory/nsaids.htm. Cited 24 June 2008

42.

US Food and Drug Administration (2005) Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. US Food and Drug Administration. Available via http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf. Cited 24 June 2008

43.

Bouchard MF, Taniguchi H, Viger RS (2005) Protein kinase A-dependent synergism between GATA factors and the nuclear receptor, liver receptor homolog-1, regulates human aromatase (CYP19) PII promoter activity in breast cancer cells. Endocrinology 146:4905–4916. doi:10.1210/en.2005-0187 PubMedCrossRef

44.

Zhou J, Suzuki T, Kovacic A et al (2005) Interactions between prostaglandin E(2), liver receptor homologue-1, and aromatase in breast cancer. Cancer Res 65:657–663PubMed

45.

Bulun SE, Sebastian S, Takayama K et al (2003) The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol 86:219–224. doi:10.1016/S0960-0760(03)00359-5 PubMedCrossRef

Title: Celecoxib and exemestane versus placebo and exemestane in postmenopausal metastatic breast cancer patients: a double-blind phase III GINECO study
Authors: C. Falandry
M. Debled
T. Bachelot
T. Delozier
J. Crétin
P. Romestaing
D. Mille
B. You
L. Mauriac
E. Pujade-Lauraine
G. Freyer
Publication date: 01-08-2009
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-008-0229-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2009

Hazard of recurrence and adjuvant treatment effects over time in lymph node-negative breast cancer

Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas

BRCA1/BRCA2 mutation status and clinical-pathologic features of 108 male breast cancer cases from Tuscany: a population-based study in central Italy

Alcohol and folate intake and breast cancer risk in the WHI Observational Study

CCND1 G870A polymorphism contributes to breast cancer susceptibility: a meta-analysis

Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH

Keynote webinar | Spotlight on antibody–drug conjugates in cancer