A randomized trial to assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 500 mg alone or anastrozole alone on primary breast cancer

John F R Robertson, J Michael Dixon, D Mark Sibbering, Ali Jahan, Ian O Ellis, Eddie Channon, Pauline Hyman-Taylor, Robert I Nicholson, Julia M W Gee, John F R Robertson, J Michael Dixon, D Mark Sibbering, Ali Jahan, Ian O Ellis, Eddie Channon, Pauline Hyman-Taylor, Robert I Nicholson, Julia M W Gee

Abstract

Introduction: Fulvestrant shows dose-dependent biological activity. Greater estrogen-receptor (ER) blockade may feasibly be achieved by combining fulvestrant with anastrozole. This pre-surgical study compared fulvestrant plus anastrozole versus either agent alone in patients with ER-positive breast cancer.

Methods: In this double-blind, multicenter trial, 121 patients received fulvestrant 500 mg on Day 1 plus anastrozole 1 mg/day for 14 to 21 days (F + A); fulvestrant plus anastrozole placebo (F); or fulvestrant placebo plus anastrozole (A), 2 to 3 weeks before surgery. ER, progesterone-receptor (PgR) and Ki67 expression were determined from tumor biopsies before treatment and at surgery.

Results: A total of 103 paired samples were available (F, n = 35; F+A, n = 31; A, n = 37). All treatments significantly reduced mean ER expression from baseline (F: -41%, P = 0.0001; F + A: -39%, P = 0.0001; A: -13%, P = 0.0034). F and F + A led to greater reductions in ER versus A (both P = 0.0001); F + A did not lead to additional reductions versus F. PgR and Ki67 expression were significantly reduced with all treatments (means were -34% to -45%, and -75% to -85%, respectively; all P = 0.0001), with no differences between groups.

Conclusions: In this short-term study, all treatments reduced ER expression, although F and F + A showed greater reductions than A. No significant differences were detected between the treatment groups in terms of PgR and Ki67 expression. No additional reduction in tumor biomarkers with combination treatment was observed, suggesting that F + A is unlikely to have further clinical benefit over F alone.

Trial registration: Clinicaltrials.gov NCT00259090.

Figures

Figure 1
Figure 1
Study design. ER, estrogen receptor.
Figure 2
Figure 2
Mean change in pre- and post-treatment data. (a) ER H-score, (b) PgR H-score and (c) Ki67 labeling index. Where the overall tests for treatment effect were not significant for total PgR H-score and Ki67 index, pairwise comparisons were deemed non-significant. Error bars represent standard error of the mean. ER, estrogen receptor; NS, not significant; PgR, progesterone receptor.
Figure 3
Figure 3
Scatter plots of individual pre- versus post-treatment data. (a) ER, (b) PgR and (c) Ki67. ER, estrogen receptor; PgR, progesterone receptor.

References

    1. Robertson JF, Nicholson RI, Bundred NJ, Anderson E, Rayter Z, Dowsett M, Fox JN, Gee JM, Webster A, Wakeling AE, Morris C, Dixon M. Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3, 17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res. 2001;61:6739–6746.
    1. Dowsett M, Nicholson RI, Pietras RJ. Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance. Breast Cancer Res Treat. 2005;93(Suppl 1):S11–S18.
    1. DeFriend DJ, Howell A, Nicholson RI, Anderson E, Dowsett M, Mansel RE, Blamey RW, Bundred NJ, Robertson JF, Saunders C, Baum H, Walton P, Sutcliffe FA, Wakeling AE. Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. Cancer Res. 1994;54:408–414.
    1. Gradishar W. Fulvestrant in the treatment of postmenopausal women with advanced breast cancer. Expert Rev Anticancer Ther. 2005;5:445–453. doi: 10.1586/14737140.5.3.445.
    1. Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20:3396–3403. doi: 10.1200/JCO.2002.10.057.
    1. Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R, Buzdar A. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002;20:3386–3395. doi: 10.1200/JCO.2002.10.058.
    1. Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, Kleeberg UR, Come SE, Vergote I, Gertler S, Buzdar A, Webster A, Morris C. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer. 2003;98:229–238. doi: 10.1002/cncr.11468.
    1. Robertson JF. Fulvestrant (Faslodex) - how to make a good drug better. Oncologist. 2007;12:774–784. doi: 10.1634/theoncologist.12-7-774.
    1. Kuter I, Gee JM, Hegg R, Singer CF, Badwe RA, Lowe ES, Emeribe UA, Anderson E, Sapunar F, Finlay P, Nicholson RI, Bines J, Harbeck N. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. Breast Cancer Res Treat. 2012;133:237–246. doi: 10.1007/s10549-011-1947-7.
    1. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JP, Sapunar F, Martin M. Results of the CONFIRM Phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28:4594–4600. doi: 10.1200/JCO.2010.28.8415.
    1. Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, Lindemann JP, Wiklund F, Henriksson R. FACT: an open-label randomized Phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30:1919–1925. doi: 10.1200/JCO.2011.38.1095.
    1. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367:435–444. doi: 10.1056/NEJMoa1201622.
    1. Robertson JFR, Llombart A, Rolski J, Feltl D, Dewar J, Macpherson E, Lindemann J, Ellis MJ. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol. 2009;27:4530–4535. doi: 10.1200/JCO.2008.21.1136.
    1. Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, Ashley SE, Francis S, Boeddinghaus I, Walsh G. IMPACT Trialists' Group. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005;23:5108–5116. doi: 10.1200/JCO.2005.04.005.
    1. Mouridsen HT. Letrozole in advanced breast cancer: the PO25 trial. Breast Cancer Res Treat. 2007;105(Suppl 1):19–29.
    1. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, Deschryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype - ACOSOG Z1031. J Clin Oncol. 2011;29:2342–2349. doi: 10.1200/JCO.2010.31.6950.
    1. Macedo L, Sabnis G, Goloubeva O, Brodie A. Combination of anastrozole with fulvestrant in the intratumoral aromatase xenograft model. Cancer Res. 2008;68:3516–3522. doi: 10.1158/0008-5472.CAN-07-6807.
    1. Johnston S, Kilburn LS, Ellis P, Cameron D, Dodwell D, Howell A, Im YH, Coombes G, Dowsett M, Bliss JM. Fulvestrant alone or with concomitant anastrozole vs exemestane following progression on non-steroidal aromatase inhibitor - first results of the SoFEa trial. Eur J Cancer. 2012;48(Suppl 3):S2.
    1. Robertson JFR, Lindemann J, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, Emerson L, Dean A, Ellis MJ. A comparison of fulvestrant 500 mg with anastrozole as first-line treatment for advanced breast cancer: follow-up analysis from the 'FIRST' study. Cancer Res. 2010;70(Suppl) Abstract S1-3.
    1. Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96:926–935. doi: 10.1093/jnci/djh166.
    1. Martin LA, Farmer I, Johnston SR, Ali S, Dowsett M. Elevated ERK1/ERK2/estrogen receptor cross-talk enhances estrogen-mediated signaling during long-term estrogen deprivation. Endocr Relat Cancer. 2005;12(Suppl 1):S75–S84.
    1. Staka CM, Nicholson RI, Gee JM. Acquired resistance to oestrogen deprivation: role for growth factor signalling kinases/oestrogen receptor cross-talk revealed in new MCF-7X model. Endocr Relat Cancer. 2005;12(Suppl 1):S85–S97.
    1. Britton DJ, Hutcheson IR, Knowlden JM, Barrow D, Giles M, McClelland RA, Gee JM, Nicholson RI. Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat. 2006;96:131–146. doi: 10.1007/s10549-005-9070-2.
    1. Kuter I, Sapunar F, McCormack P. Pharmacokinetic profile of fulvestrant 500 mg vs 250 mg: results from the NEWEST study. J Clin Oncol. 2008;26(Suppl) Abstract 579.
    1. Rose C, Kamby C, Mouridsen HT, Bastholt L, Brincker H, Skovgaard-Poulsen H, Andersen AP, Loft H, Dombernowsky P, Andersen KW. Combined endocrine treatment of postmenopausal patients with advanced breast cancer. A randomized trial of tamoxifen vs. tamoxifen plus aminoglutethimide and hydrocortisone. Breast Cancer Res Treat. 1986;7(Suppl):S45–S50.
    1. Ingle JN, Green SJ, Ahmann DL, Long HJ, Edmonson JH, Rubin J, Chang MN, Creagan ET. Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer. J Clin Oncol. 1986;4:958–964.
    1. Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131–2139.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다