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01-06-2013 | Epidemiology

Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer

Authors: Jennifer Karle, Juliane Bolbrinker, Silvia Vogl, Reinhold Kreutz, Carsten Denkert, Jan Eucker, Manfred Wischnewsky, Kurt Possinger, Anne C. Regierer

Published in: Breast Cancer Research and Treatment | Issue 2/2013

Abstract

The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29–90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15–4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12–6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.

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Title: Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer
Authors: Jennifer Karle
Juliane Bolbrinker
Silvia Vogl
Reinhold Kreutz
Carsten Denkert
Jan Eucker
Manfred Wischnewsky
Kurt Possinger
Anne C. Regierer
Publication date: 01-06-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-013-2565-3

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