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Anastrozole Dose Escalation for Optimal Estrogen Suppression in Postmenopausal Women With Early-Stage Breast Cancer
TAKE-HOME MESSAGE
- This prospective trial showed that 30% of postmenopausal women with ER-positive early-stage breast cancer treated with anastrozole had estrone (E1) and estradiol (E2) levels above the thresholds that were previously shown to be associated with an elevated risk of early breast cancer recurrence. High-dose anastrozole (10 mg/day) led to the suppression of E1 and E2 levels below these thresholds in the majority of women (76%) adherent to therapy. Additionally, no dose-limiting toxicities or grade 3 and higher adverse events were observed with the 10-mg dosing.
- E1 and E2 may serve as biomarkers to help individualize anastrozole dosing and improve outcomes for postmenopausal women with ER-positive early-stage breast cancer. Further study is required to validate the proper threshold for estrogen suppression in patients taking anastrozole in the adjuvant setting.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
We previously reported that postmenopausal women with ER+ breast cancer (BC) receiving adjuvant anastrozole 1 mg/day (ANA1) with estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 (inadequate estrogen suppression [IES]) had a 3.0-fold increased risk of a BC event. The objective of this study was to determine if increasing anastrozole to 10 mg/day (ANA10) could result in adequate estrogen suppression (AES: E1 <1.3 pg/mL and/or E2 <0.5) among those with IES on ANA1.
METHODS
Postmenopausal women with ER+ BC planning to receive adjuvant ANA1 were eligible. E1 and E2 were assessed pre- and post-8-10 weeks of ANA1. Those with IES were switched to 8-10 week cycles of ANA10 followed by letrozole 2.5 mg/day. E1 and E2 were assessed after each cycle. Anastrozole concentrations were measured post-ANA1 and post-ANA10. Primary analyses included patients who documented taking at least 80% of planned treatment (adherent cohort).
RESULTS
132 (84.6%) of 156 eligible patients were ANA1-adherent. IES occurred in 40 (30.3%) adherent patients. 25 (78.1%) of 32 patients who began ANA10 were adherent, and AES was achieved in 19 (76.0%; 90%CI: 58.1-89.0%) patients. Anastrozole concentrations post-ANA1 and post-ANA10 did not differ by estrogen suppression status among adherent patients. AES was maintained/attained in 21 (91.3%) of 23 letrozole-adherent patients.
CONCLUSIONS
Approximately 30% of ANA1-adherent patients had IES. Among those who switched to ANA10 and were adherent, 76% had AES. Further studies are required to validate emerging data that ANA1 results in IES for some patients and to determine the clinical benefit of switching to ANA10 or an alternative AI.
Additional Info
Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early-stage breast cancer: A prospective trial
Clin. Cancer Res 2024 May 16;[EPub Ahead of Print], TC Haddad, VJ Suman, KV Giridhar, K Sideras, DW Northfelt, BJ Ernst, CC O'Sullivan, RJ Singh, Z Desta, PP Peethambaram, TJ Hobday, S Chumsri, RA Leon-Ferre, KJ Ruddy, S Yadav, JL Taraba, B Goodnature, MP Goetz, L Wang, JN IngleFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Although prior phase III breast cancer clinical trials comparing the three aromatase inhibitors (AIs; anastrozole, exemestane, and letrozole) as adjuvant endocrine therapy did not identify significant differences in long-term clinical outcomes, substantial interindividual variability exists in the pharmacodynamic effect of the AIs on estrone (E1) and estradiol (E2) levels. Notably, in the MA.271 and PreFace2 trials, postmenopausal women on anastrozole with inadequate estrogen suppression (defined as E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL) had a threefold higher risk for a breast cancer event, whereas no similar association was found with exemestane or letrozole.
In this prospective pharmacodynamic study, 30% of postmenopausal women receiving standard-dose anastrozole (1 mg/day) were found to have inadequate estrogen suppression. Among them, 76% achieved adequate estrogen suppression of E1 and E2 levels with high-dose anastrozole (10 mg/day), and this dose was well-tolerated. Furthermore, adequate estrogen suppression was maintained or attained in 91.3% of participants when switched from high-dose anastrozole to standard-dose letrozole (2.5 mg/day).
This study challenges the notion that standard-dose anastrozole is appropriate for all patients. Tailoring AI dose levels to achieve adequate estrogen suppression may be necessary to optimize the drugs' therapeutic benefit. This study further raises the question of whether E1 and E2 levels should be routinely assessed in patients receiving adjuvant AIs, and it asserts the need to implement more sensitive quantitation methods in clinical practice.
A deeper understanding of the pharmacodynamic effect of AIs on estrogen suppression is critical, as drug selection and E1 and E2 levels may directly impact a patient’s risk of breast cancer recurrence. If prospective validation of the proposed threshold for suppressing E1 and E2 is accomplished, these levels may serve as biomarkers of prognosis and AI efficacy in postmenopausal women with early-stage ER-positive breast cancer.
References