Superior suppression of serum estrogens during neoadjuvant breast cancer treatment with letrozole compared to exemestane

Abstract

Purpose: The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast cancer in all phases of the disease. Although both drugs inhibit CYP19 (aromatase) and have been used for decades, a direct head-to-head, intra-patient-cross-over comparison of their ability to decrease estrogen synthesis in vivo is still lacking.

Methods: Postmenopausal breast cancer patients suitable for neoadjuvant endocrine therapy were randomized to receive either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for an initial treatment period, followed by a second treatment period on the alternative drug (intra-patient cross-over study design). Serum levels of estrone (E1), estradiol (E2), letrozole, exemestane, and 17-hydroxyexemestane were quantified simultaneously using a novel, ultrasensitive LC-MS/MS method established in our laboratory.

Results: Complete sets of serum samples (baseline and during treatment with letrozole or exemestane) were available from 79 patients, including 40 patients starting with letrozole (cohort 1) and 39 with exemestane (cohort 2). Mean serum estrone and estradiol levels in cohort 1 were 174 pmol/L and 46.4 pmol/L at baseline, respectively. Treatment with letrozole suppressed serum E1 and E2 to a mean value of 0.2 pmol/L and 0.4 pmol/L (P < 0.001). After the cross-over to exemestane, mean serum levels of E1 and E2 increased to 1.4 pmol/L and 0.7 pmol/L, respectively. In cohort 2, baseline mean serum levels of E1 and E2 were 159 and 32.5 pmol/L, respectively. Treatment with exemestane decreased these values to 1.8 pmol/L for E1 and 0.6 pmol/L for E2 (P < 0.001). Following cross-over to letrozole, mean serum levels of E1 and E2 were significantly further reduced to 0.1 pmol/L and 0.4 pmol/L, respectively. Serum drug levels were monitored in all patients throughout the entire treatment and confirmed adherence to the protocol and drug concentrations within the therapeutic range for all patients. Additionally, Ki-67 values decreased significantly during treatment with both aromatase inhibitors, showing a trend toward a stronger suppression in obese women.

Conclusion: To the best of our knowledge, we present here for the first time a comprehensive and direct head-to-head, intra-patient-cross-over comparison of the aromatase inhibitor letrozole and the aromatase inactivator exemestane concerning their ability to suppress serum estrogen levels in vivo. All in all, our results clearly demonstrate that letrozole therapy results in a more profound suppression of serum E1 and E2 levels compared to exemestane.

Keywords: Aromatase; Breast cancer; Estrogens; Exemestane; Letrozole; Neoadjuvant.

Fig. 1

Schematic overview of The NEOLETEXE-trial—neoadjuvant, treatment with letrozole and exemestane in a randomized sequence

Fig. 2

Statistical overview of serum measurements. The figure presents mean values, ranges, and medians for serum levels of Estradiol (E2), Estrone (E1), Exemestane (EXE), 17-hydroxy-exemestane (17HEXE), and Letrozole (LET). P values are calculated comparing each treatment phase to its preceding period (i.e., baseline to treatment 1 and treatment 1 to treatment 2) within each cohort

Fig. 3

Individual changes in serum estrogen concentrations across treatment periods. Variations in serum levels of estrone and estradiol for individual patients in both cohorts during treatment with either letrozole or exemestane are depicted. P values are calculated comparing each treatment phase to its preceding phase (i.e., baseline to treatment 1 and treatment 1 to treatment 2) within each cohort. The black dashed line represents the lower limit of quantification divided by 2, specifically 0.2 pmol/L for estrone and 0.8 pmol/L for estradiol

Fig. 4

Correlation matrix of key parameters. The matrix displays the correlations between BMI, baseline and treatment-specific levels of estradiol (E2), estrone (E1), letrozole (LET), exemestane (EXE), 17-hydroxy-exemestane (17HEXE), and changes in Ki-67 across the two treatment periods (T1 and T2). Correlations are calculated using Pearson’s r

Fig. 5

Relationship between serum drug concentrations and estrogen suppression. Graphs A and B illustrate individual patient estrone suppression from baseline to on-treatment with exemestane (graph A) or letrozole (graph B). Graphs C and D present the corresponding data for estradiol suppression. Estrone suppression is more pronounced during letrozole treatment (graph B) compared to exemestane (graph A)

Fig. 6

Correlation of serum levels of exemestane and its main active metabolite, 17-hydroxy-exemestane, across individual patients

Fig. 7

Relationship between BMI and Ki-67 suppression across treatment groups. The figure illustrates the absolute changes in Ki-67 levels in relation to patient BMI categories, stratified by treatment with either letrozole or exemestane. Median changes in Ki-67 (Q2) are represented for each BMI category within both cohorts and reflect measurements from baseline to the conclusion of the 6-month treatment period. Error bars indicate the interquartile range, extending from the first quartile (Q1) to the third quartile (Q3)