Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy

Alastair M. Thompson (1, 2) , Andrea Johnson (3) , Philip Quinlan (1) , Grantland Hillman (3) , Marcel Fontecha (3) , Susan E. Bray (1) , Colin A. Purdie (4) , Lee B. Jordan (4) , Roberta Ferraldeschi (5, 6) , Ayshe Latif (5) , Kirsten D. Hadfield (5) , Robert B. Clarke (7) , Linda Ashcroft (6) , D. Gareth Evans (5) , Anthony Howell (6) , Michele Nikoloff (3) , Jeffrey Lawrence (3) , William G. Newman (5)

1 Department of Surgery and Molecular Oncology
2 Department of Surgical Oncology
3 Roche Molecular Diagnostics
4 Department of Pathology [Dundee]
5 Genetic Medicine
6 Department of Medical Oncology
7 Paterson Institute for Cancer Research, University of Manchester

The association between genotype and outcome in breast cancer patients treated with adjuvant tamoxifen remains controversial. We assessed the influence of comprehensive versus limited genotype in the context of tamoxifen adherence and co-medication in a large cohort of 618 patients. Genotyping of 33 alleles used two archival cohorts from tamoxifen-treated women with invasive breast cancer (Dundee,  = 391; Manchester,  = 227). Estimates for recurrence-free survival (RFS) were calculated based on inferred CYP2D6 phenotypes using Kaplan–Meier and Cox proportional hazard models, adjusted for nodal status and tumour size. Patients with at least one reduced function allele (60%) or no functional alleles (6%) had a non-significant trend for worse RFS: hazard ratio (HR) 1.52 (CI 0.98–2.36,  = 0.06). For post-menopausal women on tamoxifen monotherapy, the HR for recurrence in patients with reduced functional alleles was 1.96 (CI 1.05–3.66,  = 0.036). However, RFS analysis limited to four common allelic variants was no longer significant ( = 0.39). The effect of genotype was increased by adjusting for adherence to tamoxifen therapy, but not significantly changed when adjusted for co-administration of potent inhibitors of CYP2D6. Comprehensive genotyping of and adherence to tamoxifen therapy may be useful to identify breast cancer patients most likely to benefit from adjuvant tamoxifen.

Mots clés: Adherence; Cytochrome P450; CYP2D6; Pharmacogenetics; Tamoxifen

Alastair M. Thompson, Andrea Johnson, Philip Quinlan, Grantland Hillman, Marcel Fontecha, et al.. Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy. Breast Cancer Research and Treatment, 2010, 125 (1), pp.279-287. ⟨10.1007/s10549-010-1139-x⟩. ⟨hal-00570705⟩