Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor–Positive Breast Cancer

Author(s): Davide Serrano, MD1; Sara Gandini, PhD1; Parjhitham Thomas, MD2; Katherine D. Crew, MD, MS3; Nagi B. Kumar, PhD, RD4; Lana A. Vornik, MHA, MS2; J. Jack Lee, PhD2; Paolo Veronesi, MD1; Giuseppe Viale, MD1; Aliana Guerrieri-Gonzaga, MSc1; Matteo Lazzeroni, MD1; Harriet Johansson, PhD1; Mauro D’Amico, MD5; Flavio Guasone, MD6; Stefano Spinaci, MD6; Bjørn-Erik Bertelsen, MSc7; Gunnar Mellgren, MD, PhD7,8; Isabelle Bedrosian, MD2; Diane Weber, RN2; Tawana Castile, BS, CCRP2; Eileen Dimond, RN, MS9; Brandy M. Heckman-Stoddard, PhD, MPH9; Eva Szabo, MD9; Powel H. Brown, MD, PhD2; Andrea DeCensi, MD5,10; Bernardo Bonanni, MD1
Source: JAMA Oncol. 2023;9(5):664-672. doi:10.1001/jamaoncol.2023.0089
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Alternative dosing of exemestane given TIW vs. once weekly treatment in adjuvant breast cancer, end-point was serum estradiol measurements and not survival metrics. Would like to see this done on a larger scale or with other end-points, but for those who are not tolerating standard dosing, this could be an option to consider.

IMPORTANCE

Successful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events.

OBJECTIVE

To compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor–positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of −6%.

DESIGN, SETTING, AND PARTICIPANTS

This multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor–positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021.

INTERVENTIONS

Exemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery.

MAIN OUTCOMES AND MEASURES

Serum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography–tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry.

RESULTS

A total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was −89%, −85%, and −60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was −3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, −5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of −7.5%, −5.0%, and −4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and −17.0%, −9.0%, and −7.0% for progesterone receptor, respectively. Sex hormone–binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms.

CONCLUSIONS AND RELEVANCE

In this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting.

Author Affiliations

1European Institute of Oncology IRCCS, Milan, Italy2The University of Texas MD Anderson Cancer Center, Houston3Columbia University Irving Medical Center, New York, New York4Moffitt Cancer Center, University of South Florida, Tampa5Ospedali Galliera, Genoa, Italy6Ospedale Villa Scassi ASL3, Genoa, Italy7Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway8Department of Clinical Science, University of Bergen, Bergen, Norway9Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland10Wolfson Institute of Population Health, Queen Mary University of London, London, England, United Kingdom

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