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Item Anastrozole has an association between degree of estrogen suppression and outcomes in early breast cancer and is a ligand for estrogen receptor α(American Association of Cancer Research, 2020-06-15) Ingle, James N.; Cairns, Junmei; Suman, Vera J.; Shepherd, Lois E.; Fasching, Peter A.; Hoskin, Tanya L.; Singh, Ravinder J.; Desta, Zeruesenay; Kalari, Krishna R.; Ellis, Matthew J.; Goss, Paul E.; Chen, Bingshu E.; Volz, Bernhard; Barman, Poulami; Carlson, Erin E.; Haddad, Tufia; Goetz, Matthew P.; Goodnature, Barbara; Cuellar, Matthew E.; Walters, Michael A.; Correia, Cristina; Kaufmann, Scott H.; Weinshilboum, Richard M.; Wang, Liewei; Medicine, School of MedicinePurpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental design: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. Conclusions: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.Item Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole(AACR, 2011-12) Prowell, Tatiana M.; Blackford, Amanda L.; Byrne, Celia; Khouri, Nagi F.; Dowsett, Mitchell; Folkerd, Elizabeth; Tarpinian, Karineh S.; Powers, Pendleton P.; Wright, Laurie A.; Donehower, Michele G.; Jeter, Stacie C.; Armstrong, Deborah K.; Emens, Leisha A.; Fetting, John H.; Wolff, Antonio C.; Garrett-Mayer, Elizabeth; Skaar, Todd C.; Davidson, Nancy E.; Stearns, VeredFactors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes.