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

Matthew Philip Goetz, Vera Jean 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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Cytochrome P-450 CYP2D6
Tamoxifen
Colorectal Neoplasms
Alleles
Breast Neoplasms
Confidence Intervals
Estrogen Receptors
Case-Control Studies
Neoplasms
Research Design
Genotype
Radiation
Neoplasm Metastasis
Recurrence
Therapeutics
anastrozole

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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CYP2D6 metabolism and patient outcome in the Austrian breast and colorectal cancer study group trial (ABCSG) 8. / Goetz, Matthew Philip; Suman, Vera Jean; Hoskin, Tanya L.; Gnant, Michael; Filipits, Martin; Safgren, Stephanie L.; Kuffel, Mary; Jakesz, Raimund; Rudas, Margaretha; Greil, Richard; Dietze, Otto; Lang, Alois; Offner, Felix; Reynolds, Carol A.; Weinshilboum, Richard M; Ames, Matthew M.; Ingle, James N.

In: Clinical Cancer Research, Vol. 19, No. 2, 15.01.2013, p. 500-507.

Research output: Contribution to journalArticle

Goetz, MP, Suman, VJ, Hoskin, TL, Gnant, M, Filipits, M, Safgren, SL, Kuffel, M, Jakesz, R, Rudas, M, Greil, R, Dietze, O, Lang, A, Offner, F, Reynolds, CA, Weinshilboum, RM, Ames, MM & Ingle, JN 2013, 'CYP2D6 metabolism and patient outcome in the Austrian breast and colorectal cancer study group trial (ABCSG) 8', Clinical Cancer Research, vol. 19, no. 2, pp. 500-507. https://doi.org/10.1158/1078-0432.CCR-12-2153
Goetz, Matthew Philip ; Suman, Vera Jean ; Hoskin, Tanya L. ; Gnant, Michael ; Filipits, Martin ; Safgren, Stephanie L. ; Kuffel, Mary ; Jakesz, Raimund ; Rudas, Margaretha ; Greil, Richard ; Dietze, Otto ; Lang, Alois ; Offner, Felix ; Reynolds, Carol A. ; Weinshilboum, Richard M ; Ames, Matthew M. ; Ingle, James N. / CYP2D6 metabolism and patient outcome in the Austrian breast and colorectal cancer study group trial (ABCSG) 8. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 2. pp. 500-507.
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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.",
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T1 - CYP2D6 metabolism and patient outcome in the Austrian breast and colorectal cancer study group trial (ABCSG) 8

AU - Goetz, Matthew Philip

AU - Suman, Vera Jean

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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