TY - JOUR
T1 - CYP2D6 metabolism and patient outcome in the Austrian breast and colorectal cancer study group trial (ABCSG) 8
AU - Goetz, Matthew P.
AU - Suman, Vera J.
AU - Hoskin, Tanya L.
AU - Gnant, Michael
AU - Filipits, Martin
AU - Safgren, Stephanie L.
AU - Kuffel, Mary
AU - Jakesz, Raimund
AU - Rudas, Margaretha
AU - Greil, Richard
AU - Dietze, Otto
AU - Lang, Alois
AU - Offner, Felix
AU - Reynolds, Carol A.
AU - Weinshilboum, Richard M.
AU - Ames, Matthew M.
AU - Ingle, James N.
PY - 2013/1/15
Y1 - 2013/1/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-12-2153
DO - 10.1158/1078-0432.CCR-12-2153
M3 - Article
C2 - 23213055
AN - SCOPUS:84872580456
SN - 1078-0432
VL - 19
SP - 500
EP - 507
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -