Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer

James N. Ingle, Aman U. Buzdar, Daniel J Schaid, Matthew Philip Goetz, Anthony Batzler, Mark E. Robson, Donald W Northfelt, Janet E Olson, Edith A. Perez, Zeruesenay Desta, Randy A. Weintraub, Clark V. Williard, David A. Flockhart, Richard M Weinshilboum

Research output: Contribution to journalArticle

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Abstract

Aromatase inhibitors play a prominent role in the management of postmenopausal women with endocrinesensitive breast cancer, but there is large variability in both efficacy and tolerability. The purpose of our study was to define interindividual variation in anastrozole metabolism and pharmacodynamics among patients treated with the approved daily dose of 1 mg in a standard practice setting as adjuvant therapy for resected early breast cancer. This study was performed in 191 women in whom pretreatment and during anastrozole plasma concentrations of estrone (E1), estradiol (E2), estrone conjugates, androstenedione, and testosterone were determined and correlated with plasma concentrations of anastrozole and anastrozole metabolites. There were large interindividual variations in plasma anastrozole and anastrozole metabolite concentrations, as well as pretreatment and postdrug plasma E1, E2, and E1 conjugate and estrogen precursor (androstenedione and testosterone) concentrations. E1 and E2 concentrations were below the lower limit of quantitation (LLQ) in most patients after anastrozole therapy (83% for both), but those with detectable concentrations had a broad range (1.58-45.2 and 0.635-97.0 pg/mL, respectively). E1 conjugates after anastrozole therapy were above the LLQ in most patients (93%), with wide interpatient variability (3.50-2,990 pg/mL). Two patients seemed to extensively metabolize anastrozole and failed to display substantial decreases in estrogens. Acknowledging the potential factor of variable compliance, our results showed large interindividual variation in anastrozole metabolism and its effect on circulating estrogens in postmenopausal patients. These findings may have implications with regard to efficacy and adverse events and may indicate the need to "individualize" therapy with this drug.

Original languageEnglish (US)
Pages (from-to)3278-3286
Number of pages9
JournalCancer Research
Volume70
Issue number8
DOIs
StatePublished - Apr 15 2010

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Breast Neoplasms
Estrogens
Androstenedione
Estrone
Testosterone
anastrozole
Aromatase Inhibitors
Compliance
Estradiol
Therapeutics
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer. / Ingle, James N.; Buzdar, Aman U.; Schaid, Daniel J; Goetz, Matthew Philip; Batzler, Anthony; Robson, Mark E.; Northfelt, Donald W; Olson, Janet E; Perez, Edith A.; Desta, Zeruesenay; Weintraub, Randy A.; Williard, Clark V.; Flockhart, David A.; Weinshilboum, Richard M.

In: Cancer Research, Vol. 70, No. 8, 15.04.2010, p. 3278-3286.

Research output: Contribution to journalArticle

Ingle, JN, Buzdar, AU, Schaid, DJ, Goetz, MP, Batzler, A, Robson, ME, Northfelt, DW, Olson, JE, Perez, EA, Desta, Z, Weintraub, RA, Williard, CV, Flockhart, DA & Weinshilboum, RM 2010, 'Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer', Cancer Research, vol. 70, no. 8, pp. 3278-3286. https://doi.org/10.1158/0008-5472.CAN-09-3024
Ingle, James N. ; Buzdar, Aman U. ; Schaid, Daniel J ; Goetz, Matthew Philip ; Batzler, Anthony ; Robson, Mark E. ; Northfelt, Donald W ; Olson, Janet E ; Perez, Edith A. ; Desta, Zeruesenay ; Weintraub, Randy A. ; Williard, Clark V. ; Flockhart, David A. ; Weinshilboum, Richard M. / Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer. In: Cancer Research. 2010 ; Vol. 70, No. 8. pp. 3278-3286.
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