Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98

Dieter Koeberle, Beat Thuerlimann, Dieter Koeberle, Beat Thuerlimann

Abstract

The BIG 1-98 trial is a large, randomized, independently conducted clinical trial designed to compare the efficacy of upfront letrozole versus tamoxifen monotherapy and to compare sequential or up-front use of letrozole and/or tamoxifen as an early adjuvant therapy for patients with early breast cancer. We report on the results from the primary core analysis of the BIG 1-98 trial of 8,010 patients, which compares monotherapy with letrozole versus tamoxifen. This pre-planned core analysis allowed the use of patient data from the monotherapy arms of letrozole and tamoxifen and from the sequential arms prior to the drug switch point. Patients randomized to letrozole had a 19% improved disease-free survival (hazard ratio [HR]=0.81; P=0.003), due especially to reduced distant metastases (HR=0.73; P=0.001). A 14% risk reduction of fatal events in favor of letrozole was also observed (P=NS). The results from the monotherapy arms alone confirmed the findings from the primary core analysis. Based on the results from this trial, the aromatase inhibitor letrozole (Femara) is currently recommended as a part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer and has recently been approved in the early adjuvant setting in both Europe and the United States. A subsequent analysis after additional follow-up will address the question of monotherapy versus sequential therapy.

Figures

Fig. 1
Fig. 1
BIG-98 trial design
Fig. 2
Fig. 2
CONSORT (Consolidated Standards of Reporting Trials) flowchart of the BIG 1-98 trial. The primary core analysis includes all 8,010 assessable patients, but events and follow-up in the sequential treatment groups (L → T and T → L) are truncated at 30 days after switching to the other treatment. L denotes letrozole and T tamoxifen. Reprinted from [, Supplementary Appendix]
Fig. 3
Fig. 3
Cumulative incidence of a breast cancer relapse in the BIG 1-98 trial. Reprinted from [18] with permission from the Massachusetts Medical Society
Fig. 4
Fig. 4
Cox proportional-hazards model of data from the BIG 1-98 trial. The size of the boxes is inversely proportional to the standard error of the hazard ratio. The dashed vertical shows the hazard-ratio estimate for the overall analysis of the primary study end point (disease-free survival). Reprinted from [18] with permission from the Massachusetts Medical Society

References

    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/S0140-6736(05)66544-0', 'is_inner': False, 'url': 'https://doi.org/10.1016/s0140-6736(05)66544-0'}, {'type': 'PubMed', 'value': '15894097', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15894097/'}]}
    2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/j.ejca.2006.10.020', 'is_inner': False, 'url': 'https://doi.org/10.1016/j.ejca.2006.10.020'}, {'type': 'PubMed', 'value': '17223541', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/17223541/'}]}
    2. Demonty G, Bernard-Marty C, Puglisi F, Mancini I, Piccart M (2007) Progress and new standards of care in the management of HER-2 positive breast cancer. Eur J Cancer 43:497–509
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '7266969', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/7266969/'}]}
    2. Boccardo F, Bruzzi P, Rubagotti A, Nicolo GU, Rosso R (1981) Estrogen-like action of tamoxifen on vaginal epithelium in breast cancer patients. Oncology 38:281–285
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '6798066', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/6798066/'}]}
    2. Helgason S, Wilking N, Carlstrom K, Damber MG, von Schoultz B (1982) A comparative study of the estrogenic effects of tamoxifen and 17 beta-estradiol in postmenopausal women. J Clin Endocrinol Metab 54:404–408
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1023/B:BREA.0000003957.54851.11', 'is_inner': False, 'url': 'https://doi.org/10.1023/b:brea.0000003957.54851.11'}, {'type': 'PubMed', 'value': '14692654', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14692654/'}]}
    2. Ellmen J, Hakulinen P, Partanen A, Hayes DF (2003) Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res Treat 82:103–111
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/jnci/86.7.527', 'is_inner': False, 'url': 'https://doi.org/10.1093/jnci/86.7.527'}, {'type': 'PubMed', 'value': '8133536', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/8133536/'}]}
    2. Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM (1994) Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86:527–537
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '8874334', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/8874334/'}]}
    2. Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J (1996) Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14:2731–2737
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15477543', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15477543/'}]}
    2. Bushnell CD, Goldstein LB (2004) Risk of ischemic stroke with tamoxifen treatment for breast cancer: a meta-analysis. Neurology 63:1230–1233
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/jnci/93.9.684', 'is_inner': False, 'url': 'https://doi.org/10.1093/jnci/93.9.684'}, {'type': 'PubMed', 'value': '11333290', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11333290/'}]}
    2. Fisher B, Dignam J, Bryant J, Wolmark N (2001) Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93:684–690
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/s10549-004-3777-3', 'is_inner': False, 'url': 'https://doi.org/10.1007/s10549-004-3777-3'}, {'type': 'PubMed', 'value': '15803359', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15803359/'}]}
    2. Anderson WF, Jatoi I, Devesa SS (2005) Distinct breast cancer incidence and prognostic patterns in the NCI’s SEER program: suggesting a possible link between etiology and outcome. Breast Cancer Res Treat 90:127–137
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1634/theoncologist.9-5-489', 'is_inner': False, 'url': 'https://doi.org/10.1634/theoncologist.9-5-489'}, {'type': 'PubMed', 'value': '15477633', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15477633/'}]}
    2. Mouridsen H, Sun Y, Gershanovich M, Perez-Carrion R, Becquart D, Chaudri-Ross HA, Lang R (2004) Superiority of letrozole to tamoxifen in the first-line treatment of advanced breast cancer: evidence from metastatic subgroups and a test of functional ability. Oncologist 9:489–496
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1200/JCO.2003.04.194', 'is_inner': False, 'url': 'https://doi.org/10.1200/jco.2003.04.194'}, {'type': 'PubMed', 'value': '12775735', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12775735/'}]}
    2. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A (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
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '11078488', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11078488/'}]}
    2. Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M (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 (2000). J Clin Oncol 18:3758–3767
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '11078487', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11078487/'}]}
    2. Bonneterre J, Thürlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M (2000) Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18:3748–3757
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/annonc/mdg362', 'is_inner': False, 'url': 'https://doi.org/10.1093/annonc/mdg362'}, {'type': 'PubMed', 'value': '12954578', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12954578/'}]}
    2. Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, Biganzoli L, Cufer T, Duchateau L, Hamilton A, Lobelle JP, Piccart M (2003) Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol 14:1391–1398
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '14559846', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14559846/'}]}
    2. Ellis MJ, Coop A, Singh B, Tao Y, Llombart-Cussac A, Janicke F, Mauriac L, Quebe-Fehling E, Chaudri-Ross HA, Evans DB, Miller WR (2003) Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res 63:6523–6531
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15026471', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15026471/'}]}
    2. Long BJ, Jelovac D, Handratta V, Thiantanawat A, MacPherson N, Ragaz J, Goloubeva OG, Brodie AM (2004) Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model. J Natl Cancer Inst 96:456–465
    1. Breast International Group (BIG) 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757. Erratum in: N Engl J Med 2006;354:2200
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1200/JCO.2005.01.4829', 'is_inner': False, 'url': 'https://doi.org/10.1200/jco.2005.01.4829'}, {'type': 'PubMed', 'value': '16234518', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/16234518/'}]}
    2. Dowsett M, Cuzick J, Wale C, Howell T, Houghton J, Baum M (2005) Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: an hypothesis-generating study. J Clin Oncol 23:7512–7517
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1309/H905-HYC1-6UQQ-981P', 'is_inner': False, 'url': 'https://doi.org/10.1309/h905-hyc1-6uqq-981p'}, {'type': 'PubMed', 'value': '11190807', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11190807/'}]}
    2. Rhodes A, Jasani B, Balaton AJ, Barnes DM, Anderson E, Bobrow LG, Miller KD (2001) Study of interlaboratory reliability and reproducibility of estrogen and progesterone receptor assays in Europe: documentation of poor reliability and identification of insufficient microwave antigen retrieval time as a major contributory element of unreliable assays. Am J Clin Pathol 115:44–58
    1. Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell’Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Thürlimann B, Viale G for the BIG 1-98 Collaborative Group, the IBCSG (2007) Central assessment of ER, PgR and HER2 in BIG 1-98 evaluating letrozole (L) vs. tamoxifen (T) as initial adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. J Clin Oncol 25(18S):12S. Abstract 538
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/annonc/mdm001', 'is_inner': False, 'url': 'https://doi.org/10.1093/annonc/mdm001'}, {'type': 'PubMed', 'value': '17301074', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/17301074/'}]}
    2. Mauriac L, Keshaviah A, Debled M, Mouridsen H, Forbes J, Thuerlimann B, Paridaens R, Gelber R, Castiglione-Gertsch M, Goldhirsch A (2007) Predictors of early recurrence in postmenopausal women with hormone receptor positive breast cancer in the BIG 1-98 trial. Ann Oncol 18:859–867
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1200/JCO.2006.08.8617', 'is_inner': False, 'url': 'https://doi.org/10.1200/jco.2006.08.8617'}, {'type': 'PubMed', 'value': '17200148', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/17200148/'}]}
    2. Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A (2007) Five years of letrozole versus tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: further analyses and update of study BIG 1-98. J Clin Oncol 25:486–492
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '17998546', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/17998546/'}]}
    2. Coates AS, Mourisdsen H, Sun Z, Rabaglio M, Castiglione-Gertsch M, Thürlimann B, Mauriac L, Price KN, Colleoni M, Smith I (2007) Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: updated safety analysis of trial BIG 1-98. J Clin Oncol 25(18S):8S. Abstract 521
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '8905024', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/8905024/'}]}
    2. Chang J, Powles TJ, Ashley SE, Gregory RK, Tidy VA, Treleaven JG, Singh R (1996) The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study. Ann Oncol 7:671–675
    1. Goldhirsch A, Wood W, Gelber R, Coates A, Thürlimann B, Senn HJ, and Panel members (2007) Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 18:1133–1144
    1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – v.1.2007.
    1. Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T; ATAC Trialists’ Group (2002) 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 359:2131–2139. Erratum in: Lancet 2002;360:1520
    1. Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, Sahmoud T; The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group (2003) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802–1810
    1. De Boer R, Burris H, Monnier A, Mouridsen H, O’Shaughnessy J, McIntyre K, Pritchard K, Smith I, Yardley D, on behalf of the H2H trial steering committee (2006) The Head to Head trial: letrozole vs anastrozole as adjuvant treatment of postmenopausal patients with node positive breast cancer. J Clin Oncol 24(18S):582s. Abstract 10672
    1. International Breast Cancer Study Group.
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/j.critrevonc.2005.05.005', 'is_inner': False, 'url': 'https://doi.org/10.1016/j.critrevonc.2005.05.005'}, {'type': 'PubMed', 'value': '16337805', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/16337805/'}]}
    2. Geisler J, Lønning PE (2006) Aromatase inhibitors as adjuvant treatment of breast cancer. Crit Rev Oncol Hematol 57:53–61
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '16145047', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/16145047/'}]}
    2. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262–1271
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1200/JCO.20.3.751', 'is_inner': False, 'url': 'https://doi.org/10.1200/jco.20.3.751'}, {'type': 'PubMed', 'value': '11821457', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11821457/'}]}
    2. Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE (2002) Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 20:751–757
    1. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092. Erratum in: N Engl J Med 2004;351:2461
    1. Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369:559–570. Erratum in: Lancet 2007;369:906
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1056/NEJMoa032312', 'is_inner': False, 'url': 'https://doi.org/10.1056/nejmoa032312'}, {'type': 'PubMed', 'value': '14551341', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14551341/'}]}
    2. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793–1802
    1. None
    2. Jakesz R, Gnant M, Greil R, Tausch C, Samonigg H, Kwasny W, Kubista E, Stierer M, Luschin G, Mittlboeck M (2005) The benefits of sequencing adjuvant tamoxifen and anastrozole in postmenopausal women with hormone-responsive early breast cancer: 5 year-analysis of ABCSG Trial 8. Breast Cancer Res Treat 94(suppl 1):S10. Abstract 13
    1. Phase III randomized study of adjuvant exemestane versus adjuvant tamoxifen in postmenopausal women with early breast cancer. Protocol CRC-TU-TEAM. Available at: . Accessed May 29, 2007

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