“There has been a lot of interest in the development of new antiandrogens” for clinical use in patients with breast cancer,” Anthony D. Elias, MD, reported in an update on male breast cancer at the 2020 Lynn Sage Breast Cancer Symposium, sponsored by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.1 The
“Male breast cancer is more likely than female breast cancer to be estrogen receptor–positive, and almost all male breast cancers express androgen receptor.”— Anthony D. Elias, MD
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interest has been prompted by studies “that demonstrate a role for androgens” in breast cancer and that “have further shown the antiandrogen bicalutamide, which is commonly used for the treatment of prostate cancer,” may “inhibit the growth of androgen receptor–positive breast cancer cells, both in vitro and in vivo. However, bicalutamide resistance is a frequent occurrence in prostate cancer, and bicalutamide itself can have partial agonistic activity in some circumstances.”
Hence the interest in new antiandrogens.
Dr. Elias is Professor of Medicine, Martha Cannon Dear Chair for Breast Cancer Research, University of Colorado Anschutz Medical Center, Aurora.
Poorer Survival in Men Than in Women
Although male breast cancer is rare, “the major risk factors are similar to those for women, including genetic risks, age, radiation exposure, and increased exposure to estrogens through a variety of mechanisms,” Dr. Elias explained. “Male breast cancer is more likely than female breast cancer to be estrogen receptor–positive,” he noted, and almost all male breast cancers express androgen receptor.
When asked if there was an increased risk of breast cancer in men and women using testosterone, Dr. Elias replied: “There is potentially some risk in terms of estrogenic stimulus. That said, we know from the Women’s Health Initiative, for example, that estrogen alone did not seem to necessarily increase breast cancer risk in women.” Those data “would have to be extrapolated for men,” Dr. Elias noted, “but I would suggest maybe the risk isn’t that much. I worry about testosterone supplementation more from the prostate cancer point of view, particularly in older men, where the likelihood of having a prostate abnormality is very high.”
Tamoxifen: Not Aromatase Inhibitors
Diagnostic imaging and treatments are also similar in male breast cancer to those in female breast cancer. Targeted therapies, such as CDK4/6 and PI3K inhibitors, are approved for use. “Tamoxifen—and not aromatase inhibitors—is the current standard of care for adjuvant endocrine therapy.”
A German registry study matched men and women with primary breast cancer for age, stage, and chemotherapy. They found that the overall survival at 5 years was similar for men (89%) and women (85%) receiving tamoxifen, but “the men who were treated with aromatase inhibitors did significantly worse than the women,” 73% vs 85%,2 Dr. Elias reported.
“Men have been excluded from most breast cancer trials in the past,” and “if they were allowed, typically fewer than 10 men were accrued,” Dr. Elias noted. “Men were allowed on the phase III trials of fulvestrant with or without alpelisib and letrozole with or without ribociclib. For this reason, the U.S. Food and Drug Administration labeling for alpelisib and ribociclib includes men.”
Marker of Good Prognosis
Androgen receptor “is a marker of good prognosis in estrogen receptor–positive tumors. So is estrogen receptor itself, although we target it because tumor growth is dependent on it,” Dr. Elias said. Results from several studies and data sets can be interpreted as follows: “When androgen receptor takes over for estrogen receptor signaling, relative resistance to endocrine therapy ensues,” he noted.
In preclinical models, in collaboration with Dr. Jennifer Richer, the combination of fulvestrant and the androgen receptor inhibitor enzalutamide had substantial synergy, commented Dr. Elias. This supported the development of clinical trials with this combination therapy. Clinical studies in estrogen receptor–positive breast cancer included a phase I/Ib trial combining enzalutamide with exemestane, anastrozole, or fulvestrant. According to Dr. Elias, “major drug interactions were documented” with enzalutamide and the aromatase inhibitors but not with fulvestrant.3
A phase II study of double-dose exemestane, with or without enzalutamide, found that in the intent-to-treat group, the median progression-free survival was 11.8 months with enzalutamide vs 5.8 months with single-agent exemestane, Dr. Elias reported. “In an exploratory, biomarker-enriched group, related to androgen receptor signaling, the difference was greater,” he added. Another study found that the nonsteroidal agent enobosarm, a selective androgen receptor modulator, “also appeared to have some activity” in androgen receptor–positive metastatic breast cancer.4
“We embarked on a phase II trial of fulvestrant plus enzalutamide in metastatic estrogen-receptor–positive breast cancer. These patients were heavily pretreated. Of note, we obtained tumor tissues immediately prior to therapy and at 4 weeks when the two agents were at steady state,” Dr. Elias reported. “This trial has now completed accrual, and we hope to present the results at the 2020 San Antonio Breast Cancer Symposium.”
DISCLOSURE: Dr. Elias reported no conflicts of interest.
REFERENCES
2. Eggemann H, Altmann U, Costa SD, et al: Survival benefit of tamoxifen and aromatase inhibitor in male and female breast cancer. J Cancer Res Clin Oncol 144:337-341, 2018.
3. Schwartzberg LS, Yardley DA, Elias AD, et al: A phase I/Ib study of enzalutamide alone and in combination with endocrine therapies in women with advanced breast cancer. Clin Cancer Res 23:4046-4054, 2017.
4. Overmoyer B, Sanz-Altamira P, Taylor RP, et al: Enobosarm: A targeted therapy for metastatic, androgen receptor positive, breast cancer. 2014 ASCO Annual Meeting. Abstract 568.
