CYP2D6 metabolism and patient outcome in the Austrian breast and colorectal cancer study group trial (ABCSG) 8

Matthew P. Goetz, Vera J. Suman, Tanya L. Hoskin, Michael Gnant, Martin Filipits, Stephanie L. Safgren, Mary Kuffel, Raimund Jakesz, Margaretha Rudas, Richard Greil, Otto Dietze, Alois Lang, Felix Offner, Carol A. Reynolds, Richard M. Weinshilboum, Matthew M. Ames, James N. Ingle

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Abstract

Purpose: Controversy exists about CYP2D6 genotype and tamoxifen efficacy. Experimental Design: A matched case-control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/ radiation, and tumor-node-metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism. Results: The common CYP2D6*4 allele was in Hardy-Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05-5.73, P=0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67;95% CI, 0.95-2.93; P=0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86-6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03-2.30). Conclusion: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole.

Original languageEnglish (US)
Pages (from-to)500-507
Number of pages8
JournalClinical Cancer Research
Volume19
Issue number2
DOIs
StatePublished - Jan 15 2013

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Goetz, M. P., Suman, V. J., Hoskin, T. L., Gnant, M., Filipits, M., Safgren, S. L., Kuffel, M., Jakesz, R., Rudas, M., Greil, R., Dietze, O., Lang, A., Offner, F., Reynolds, C. A., Weinshilboum, R. M., Ames, M. M., & Ingle, J. N. (2013). CYP2D6 metabolism and patient outcome in the Austrian breast and colorectal cancer study group trial (ABCSG) 8. Clinical Cancer Research, 19(2), 500-507. https://doi.org/10.1158/1078-0432.CCR-12-2153