CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8

CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8

1. Matthew P Goetz1,*,
2. Vera Suman2,
3. Tanya L Hoskin3,
4. Michael Gnant4,
5. Martin Filipits5,
6. Stephanie Safgren6,
7. Mary J. Kuffel7,
8. Raimund Jakesz8,
9. Margaretha Rudas9,
10. Richard Greil10,
11. Otto Dietze11,
12. Alois Lang12,
13. Felix Offner13,
14. Carol A. Reynolds14,
15. Richard M Weinshilboum15,
16. Matthew Ames16, and
17. James N Ingle1

+ Author Affiliations

1. ¹Oncology, Mayo Clinic
2. ²Medical Oncology, Mayo Clinic Cancer Center
3. ³Biostatistics, Mayo Clinic
4. ⁴Surgery, Medical University of Vienna, Austria
5. ⁵Dept. of Medicine I, Inst. of Cancer Research, Medical University of Vienna
6. ⁶Oncol, Mayo Clinic
7. ⁷Oncology Research, Mayo Clinic
8. ⁸Department of Surgery, Medical University of Vienna
9. ⁹Department of Pathology, Medical University of Vienna
10. ¹⁰Laboratory for Immunological and Molecular Cancer Research, Laboratory for Immunological and Molecular Cancer Research, University Clinics Salzburg
11. ¹¹Department of Pathology, General Hospital Salzburg, Paracelsus Private Medical University
12. ¹²Department of Medicine, Academic Teaching Hospital Feldkirch
13. ¹³Department of Pathology, Academic Teaching Hospital Feldkirch
14. ¹⁴Pathology, Mayo Clinic
15. ¹⁵Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
16. ¹⁶Division of Oncology Research, Mayo Clinic and Foundation

1. ↵* Corresponding Author:
   Matthew P Goetz, Oncology, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55905, United States goetz.matthew@mayo.edu

Abstract

Background: Controversy exists regarding CYP2D6 genotype and tamoxifen efficacy. Methods: A matched case-control study was conducted utilizing the Austrian Breast and Colorectal Cancer Study Group Trial 8 that randomized post-menopausal women with estrogen receptor 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 TNM stage. Genotyping was performed for alleles associated with no (PM; *3, *4, *6); reduced (IM; *10, and *41); and extensive (EM: absence of these alleles) CYP2D6 metabolism. Findings: The common CYP2D6 *4 allele was in Hardy Weinberg Equilibrium. In Arm A during the first 5 years of therapy, women with 2 poor alleles (PM/PM: OR=2.45, 95% 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 3-5 when patients remained on tamoxifen (Arm A) or switched to anastrozole (Arm B), PM/PM tended towards 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.

• Received June 27, 2012.
• Revision received October 24, 2012.
• Accepted November 7, 2012.

• Copyright © 2012, American Association for Cancer Research.