Abstract
PurposeThe aromatase inactivator exemestane may cause clinical disease stabilization following progression on non-steroidal aromatase inhibitors like letrozole in patients with metastatic breast cancer, indicating that additional therapeutic effects, not necessarily related to estrogen-suppression, may be involved in this well-known “lack of cross-resistance”.MethodsPostmenopausal women with ER positive, HER-2 negative, locally advanced breast cancer were enrolled in the NEOLETEXE-trial and randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) followed by the alternative aromatase inhibitor. Serum levels of 54 cytokines, including 12 adipokines were assessed using Luminex xMAP technology (multiple ELISA).ResultsSerum levels of leptin were significantly decreased during treatment with exemestane (p < 0.001), regardless whether exemestane was given as first or second neoadjuvant therapy. In contrast, letrozole caused a non-significant increase in serum leptin levels in vivo.ConclusionsOur findings suggest an additional and direct effect of exemestane on CYP-19 (aromatase) synthesis presumably due to effects on the CYP19 promoter use that is not present during therapy with the non-steroidal aromatase inhibitor letrozole. Our findings provide new insights into the influence of clinically important aromatase inhibitors on cytokine levels in vivo that contribute to the understanding of the clinically observed lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients.Trial registrationRegistered on March 23rd 2015 in the National trial database of Norway (Registration number: REK-SØ-84-2015).
Highlights
The third-generation aromatase inhibitors (AIs) are widely used to treat estrogen receptor positive (ER +) breast cancer in postmenopausal patients in all stages of the disease [1,2,3,4,5,6].Anastrozole and letrozole belong to the type-I class of non-steroidal aromatase inhibitors binding competitively to the P450 part of the aromatase enzyme
While aromatase inhibitors are widely established as standard of care in all phases of ER positive breast cancer variants in postmenopausal women, several important questions are still unanswered concerning their basic mechanisms of action in vivo
A lack of crossresistance between non-steroidal aromatase inhibitors and steroidal aromatase inactivators has been well-documented during treatment of metastatic breast cancer [10, 12,13,14,15,16, 19, 32]. This phenomenon has caused the establishment of exemestane therapy, either as monotherapy or in concert with mTORinhibitors like everolimus, following progression on nonsteroidal AIs in the recommended treatment guidelines in many countries worldwide
Summary
The third-generation aromatase inhibitors (AIs) (anastrozole, letrozole and exemestane) are widely used to treat estrogen receptor positive (ER +) breast cancer in postmenopausal patients in all stages of the disease [1,2,3,4,5,6]. Anastrozole and letrozole belong to the type-I class of non-steroidal aromatase inhibitors binding competitively to the P450 part of the aromatase enzyme. The fundamental biochemical differences between non-steroidal and steroidal aromatase inhibitors are from a clinical point of view of particular interest as a “lack of cross-resistance” has been documented in several clinical trials [10,11,12,13,14,15,16], providing the rationale for the use of exemestane following disease progression during treatment with a non-steroidal compound like letrozole [17]. The present manuscript reports the results of a preplanned cytokine-substudy of the NEOLETEXE-trial
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