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Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial.
Lancet Oncol. 2008 Jan; 9(1):23-8.LO

Abstract

BACKGROUND

The Breast International Group (BIG) 1-98 trial (a randomised double-blind phase III trial) has shown that letrozole significantly improves disease-free survival (DFS) compared with tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. Our aim was to establish whether the benefit of letrozole versus tamoxifen differs according to the ERBB2 status of tumours.

METHODS

The BIG 1-98 trial consists of four treatment groups that compare 5 years of monotherapy with letrozole or tamoxifen, and sequential administration of one drug for 2 years followed by the other drug for 3 years. Our study includes data from the 4922 patients randomly assigned to the two monotherapy treatment groups (letrozole or tamoxifen for 5 years; 51 months median follow-up [range <1 to 90 months]). A central assessment of oestrogen receptor (ER), progesterone receptor (PgR) and ERBB2 status using paraffin-embedded primary tumour material was possible for 3650 (74%) patients. ER, PgR, and ERBB2 expression were measured by immunohistochemistry (IHC) and ERBB2-positivity was confirmed by fluorescence in-situ hybridisation (FISH). Positive staining in at least 1% of cells was considered to show presence of ER or PgR expression. Tumours were deemed ERBB2-positive if amplified by FISH, or, for the few tumours with unassessable or unavailable FISH results, if they were IHC 3+. Hazard ratios (HR) estimated by Cox modelling were used to compare letrozole with tamoxifen for DFS, which was the primary endpoint, and to assess treatment-by-covariate interactions. The BIG 1-98 trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00004205.

FINDINGS

By central assessment 7% (257 of 3650) of tumours were classified as ERBB2-positive. In 3533 patients with tumours confirmed to express ER, DFS was poorer in patients with ERBB2-positive tumours (n=239) than in those with ERBB2-negative tumours (n=3294; HR 2.09 [95% CI 1.59-2.76]; p<0.0001). There was no statistical evidence of heterogeneity in the treatment effect according to ERBB2 status of the tumour (p=0.60 for interaction), thus, letrozole improves DFS compared with tamoxifen regardless of ERBB2 status. The observed HRs were 0.62 (95% CI 0.37-1.03) for ERBB2-positive tumours and 0.72 (0.59-0.87) for ERBB2-negative tumours.

INTERPRETATION

A benefit of letrozole over tamoxifen was noted, irrespective of ERBB2 status of the tumour, and, therefore, ERBB2 status does not seem to be a selection criterion for treatment with letrozole versus tamoxifen in postmenopausal women with endocrine-responsive early breast cancer.

Authors+Show Affiliations

Department of Pathology, Nordsjaellands Hospital, Hilleroed, Denmark. bbr@noh.regionh.dkNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18083065

Citation

Rasmussen, Birgitte B., et al. "Adjuvant Letrozole Versus Tamoxifen According to Centrally-assessed ERBB2 Status for Postmenopausal Women With Endocrine-responsive Early Breast Cancer: Supplementary Results From the BIG 1-98 Randomised Trial." The Lancet. Oncology, vol. 9, no. 1, 2008, pp. 23-8.
Rasmussen BB, Regan MM, Lykkesfeldt AE, et al. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008;9(1):23-8.
Rasmussen, B. B., Regan, M. M., Lykkesfeldt, A. E., Dell'Orto, P., Del Curto, B., Henriksen, K. L., Mastropasqua, M. G., Price, K. N., Méry, E., Lacroix-Triki, M., Braye, S., Altermatt, H. J., Gelber, R. D., Castiglione-Gertsch, M., Goldhirsch, A., Gusterson, B. A., Thürlimann, B., Coates, A. S., & Viale, G. (2008). Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. The Lancet. Oncology, 9(1), 23-8.
Rasmussen BB, et al. Adjuvant Letrozole Versus Tamoxifen According to Centrally-assessed ERBB2 Status for Postmenopausal Women With Endocrine-responsive Early Breast Cancer: Supplementary Results From the BIG 1-98 Randomised Trial. Lancet Oncol. 2008;9(1):23-8. PubMed PMID: 18083065.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. AU - Rasmussen,Birgitte B, AU - Regan,Meredith M, AU - Lykkesfeldt,Anne E, AU - Dell'Orto,Patrizia, AU - Del Curto,Barbara, AU - Henriksen,Katrine L, AU - Mastropasqua,Mauro G, AU - Price,Karen N, AU - Méry,Eliane, AU - Lacroix-Triki,Magali, AU - Braye,Stephen, AU - Altermatt,Hans J, AU - Gelber,Richard D, AU - Castiglione-Gertsch,Monica, AU - Goldhirsch,Aron, AU - Gusterson,Barry A, AU - Thürlimann,Beat, AU - Coates,Alan S, AU - Viale,Giuseppe, AU - ,, Y1 - 2007/12/20/ PY - 2007/12/18/pubmed PY - 2008/1/18/medline PY - 2007/12/18/entrez SP - 23 EP - 8 JF - The Lancet. Oncology JO - Lancet Oncol VL - 9 IS - 1 N2 - BACKGROUND: The Breast International Group (BIG) 1-98 trial (a randomised double-blind phase III trial) has shown that letrozole significantly improves disease-free survival (DFS) compared with tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. Our aim was to establish whether the benefit of letrozole versus tamoxifen differs according to the ERBB2 status of tumours. METHODS: The BIG 1-98 trial consists of four treatment groups that compare 5 years of monotherapy with letrozole or tamoxifen, and sequential administration of one drug for 2 years followed by the other drug for 3 years. Our study includes data from the 4922 patients randomly assigned to the two monotherapy treatment groups (letrozole or tamoxifen for 5 years; 51 months median follow-up [range <1 to 90 months]). A central assessment of oestrogen receptor (ER), progesterone receptor (PgR) and ERBB2 status using paraffin-embedded primary tumour material was possible for 3650 (74%) patients. ER, PgR, and ERBB2 expression were measured by immunohistochemistry (IHC) and ERBB2-positivity was confirmed by fluorescence in-situ hybridisation (FISH). Positive staining in at least 1% of cells was considered to show presence of ER or PgR expression. Tumours were deemed ERBB2-positive if amplified by FISH, or, for the few tumours with unassessable or unavailable FISH results, if they were IHC 3+. Hazard ratios (HR) estimated by Cox modelling were used to compare letrozole with tamoxifen for DFS, which was the primary endpoint, and to assess treatment-by-covariate interactions. The BIG 1-98 trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00004205. FINDINGS: By central assessment 7% (257 of 3650) of tumours were classified as ERBB2-positive. In 3533 patients with tumours confirmed to express ER, DFS was poorer in patients with ERBB2-positive tumours (n=239) than in those with ERBB2-negative tumours (n=3294; HR 2.09 [95% CI 1.59-2.76]; p<0.0001). There was no statistical evidence of heterogeneity in the treatment effect according to ERBB2 status of the tumour (p=0.60 for interaction), thus, letrozole improves DFS compared with tamoxifen regardless of ERBB2 status. The observed HRs were 0.62 (95% CI 0.37-1.03) for ERBB2-positive tumours and 0.72 (0.59-0.87) for ERBB2-negative tumours. INTERPRETATION: A benefit of letrozole over tamoxifen was noted, irrespective of ERBB2 status of the tumour, and, therefore, ERBB2 status does not seem to be a selection criterion for treatment with letrozole versus tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. SN - 1474-5488 UR - https://www.unboundmedicine.com/medline/citation/18083065/Adjuvant_letrozole_versus_tamoxifen_according_to_centrally_assessed_ERBB2_status_for_postmenopausal_women_with_endocrine_responsive_early_breast_cancer:_supplementary_results_from_the_BIG_1_98_randomised_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(07)70386-8 DB - PRIME DP - Unbound Medicine ER -