The use of chemotherapy for the treatment of breast cancer can result in transient or permanent amenorrhea, and research indicates that each month of chemotherapy translates into 1.5 year of lost reproductive life. This is especially significant for women younger than 40 years, which accounts for 6% of the population diagnosed with breast cancer.
Although there are no standard strategies for preventing chemotherapy-induced ovarian failure, preclinical data indicates that gonadotropin-releasing hormone (GnRH) analogue during chemotherapy can cause temporary ovarian suppression with resulting reduced ovarian toxicity. Although its mechanisms of action are not completely understood, it has been hypothesized that GnRH analogues may protect ovarian function by interrupting FSH secretion, decreasing in utero-ovarian perfusion, activating GnRH receptors, up-regulating intragonadal antiapoptotic molecules (eg, sphingosine-I-phosphate), or protecting undifferentiated germline stem cells. Indeed, data from phase 2 studies show that 67% to 96% of women who undergo chemotherapy for breast cancer can have their ovaries protected by GnRH analogues.
To further explore this association, researchers from Italy conducted a parallel, randomized, open-label, phase 3 superiority trial across 16 sites. The study, Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6 (PROMISE-GIM6), enrolled 281 premenopausal women (between 18 and 45 years old) with stage I through stage III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Participants were randomized to receive only chemotherapy or chemotherapy plus triptorelin. Patients who received triptorelin had 3.75 mg doses administered intramuscularly at least 1 week prior to chemotherapy initiation and then every 4 weeks during the course of chemotherapy.
In their multivariate analysis, the researchers found that only treatment with triptorelin was associated with a significant reduction of the risk of developing early menopause (odds ratio = 0.28). This association was not significantly affected by the type of chemotherapy used or by patient age. In a secondary analysis, the researchers found an absolute difference of -18% between women in the chemotherapy plus triptorelin group as compared to the chemotherapy alone group. Specifically, 25.6% and 7.9% of patients in the chemotherapy alone group and the chemotherapy plus triptorelin group, respectively, experienced early menopause. The researchers further found that menses resumed in 63.3% of the group who received triptorelin and in 49.6% of the group only receiving chemotherapy.
“Our results suggest that temporarily suppressing ovarian function by administering triptorelin reduces the incidence of chemotherapy-induced early menopause,” the researchers concluded. “This treatment can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy.”
Del Mastro L, Boni L, Michelotti A, et al.
the gonadotropin-releasing hormone analogue triptorelin on the occurrence of
chemotherapy-induced early menopause in premenopausal women with breast cancer:
a randomized trial. JAMA. 2011;306(3):269-76.