MALE Breast Cancer Trial Characterises Oestradiol Changes During Hormone Therapy

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Men with hormone receptor-positive breast cancer have responses to gonadotrophin-releasing hormone analogue (GnRHa), aromatase inhibitors (AIs) and tamoxifen that are similar to those found in premenopausal women, the MALE trial investigators say. 

“The addition of GnRHa to AI or tamoxifen leads to a more profound suppression of estradiol, which is known to increase survival in premenopausal women”, say Sibylle Loibl, from Forschungs-GmbH Wismar in Neu-Isenburg, Germany, and co-workers.

They suggest in JAMA Oncology that the additional use of “GnRHa should be therefore reconsidered as a treatment option in high-risk patients and should be weighed against increased adverse effects”. 

For the phase II trial, 52 men aged a median 61.5 years old were randomly assigned to receive 6 months’ treatment with tamoxifen 20 mg/day alone, tamoxifen 20 mg/day plus GnRHa every 3 months, or exemestane 25 mg/day plus GnRHa every 3 months. One patient in each arm discontinued treatment prematurely, the researchers say.

At baseline, median 17-β-oestradiol levels did not significantly differ between the tamoxifen only, tamoxifen plus GnRHa and exemestane plus GnRHa treatments groups, at 27.0 ng/L, 33.0 ng/L and 27.5 ng/L, respectively.

The primary endpoint of oestradiol level changes in the first 3 months of treatment was reported for 52 participants. Tamoxifen users showed a 66.7% increase in median oestradiol levels to 45.0 ng/mL, whereas patients given tamoxifen plus GnRHa had an 84.9% decrease to 5.0 ng/mL and those given exemestane plus GnRHA sustained a 72.2% decrease to 7.5 ng/mL.

At the 6-month follow-up for 49 patients, the corresponding changes in median 17-β-oestradiol from baseline were a 40.7% increase to 38.0 ng/L, a 60.6% decrease to 13.0 ng/L and 63.6% decrease to 10.0 ng/mL.

Patients were asked to complete the International Index of Erectile Function (IIEF) questionnaire and the Aging Male Symptom assessment of psychological, physical and sexual well-being at baseline and again after 3 and 6 months of treatment. 

“Although neither questionnaire has been investigated specifically in cancer patients, we wanted to capture the adverse effects from testosterone and estradiol suppression as we expected that reported adverse effects will arise from hormonal changes rather than the cancer itself”, the authors explain.

The IIEF showed a significant increase in the rate of erectile dysfunction from baseline to the 6-month checkpoint (34.6 vs 61.7%) but these changes were recorded only in the  combination treatment arms, whereas tamoxifen users “did not experience a clinically meaningful change in sexual function”, the researchers report. 

Meanwhile, the Aging Male Symptom scores indicated no significant change across the study population as a whole during treatment but suggested reductions in quality of life for the men given one of the combination regimens. 

“In premenopausal women the addition of GnRHa leads to an improved disease-free survival, and in prostate cancer the use of a GnRHa improves outcomes”, Sibylle Loibl et al observe. 

“Owing to the design of the MALE study, we are not able to deliver efficacy results; nevertheless, the comparable observations should be considered when treatment initiation is discussed with the patients”, they suggest.

The authors recommend that phase III trials should further investigate the impact of GnRHa use alongside tamoxifen or an AI on both male breast cancer survival and adverse events, noting that international collaborations will be required to ensure patient numbers for such studies. 

Reference  

Reinisch M, Seiler S, Hauzenberger T, et al. Efficacy of endocrine therapy for the treatment of breast cancer in men. Results from the MALE phase 2 randomized clinical trial. JAMA Oncol; Advance online publication 4 February 2021. doi:10.1001/jamaoncol.2020.7442