Triptorelin Helps Prevent Chemotherapy-Induced Menopause in Younger Breast Cancer Patients

Administering triptorelin, a gonadotropin-releasing hormone (GnRH) analogue, to suppress ovarian function in premenopausal women undergoing chemotherapy for early-stage breast cancer can help prevent transient or permanent amenorrhea. Investigators for the PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6) study found the beneficial association between triptorelin use and resumption of menses even more pronounced among women with hormone receptor (HR)-negative breast cancer versus those with HR-positive disease [JAMA. 2011;306(3):269-276]. They cautioned that the 12-month post-chemotherapy follow-up period was not long enough, however, to determine whether the preserved ovarian function observed with triptorelin correlates with fertility preservation. The study team enrolled 281 women in PROMISE-GIM6, which they described as the largest phase 3, randomized study to investigate the long-term effects of concurrent use of a GnRH analogue and chemotherapy on ovarian function in this population. Participants were adults ≤45 years of age (median, 39 years) eligible to undergo neoadjuvant or adjuvant chemotherapy for confirmed stage I-III breast cancer without distant metastases. Women receiving prior anticancer therapy or another cancer diagnosis within the past 5 years were excluded. Patients were randomized to chemotherapy alone (n=133) or with triptorelin (n=148). Various chemotherapy regimens were used, including anthracyclines and taxanes, although most were cyclophosphamide based. Approximately 80% of patients in each group had HR-positive tumors and thus followed up chemotherapy with 5 years of tamoxifen. Patients assigned to triptorelin received a 3.75-mg intramuscular injection ≥1 week prior to starting chemotherapy, which was repeated every 4 weeks until the last chemotherapy cycle or, for those continuing with tamoxifen, until ovarian function had been suppressed for at least 2 years. The primary end point was the rate of early menopause in each group, defined as failure to resume menses within 1 year of completing chemotherapy combined with postmenopausal levels of follicle-stimulating hormone and estradiol at 1 year, which are considered more definitive indicators of nonfunctioning ovaries. According to an intent-to-treat analysis, 17% more women in the chemotherapy-only group than in the triptorelin arm experienced early menopause (25.9% vs 8.9%, respectively; P<.001), and the authors reported that treating 6 women with triptorelin could prevent 1 case of early menopause. A multivariate analysis found triptorelin to be the only variable significantly associated with a reduced risk of early menopause (odds ratio, 0.28; 95% confidence interval, 0.14-0.59; P<.001). A secondary analysis of evaluable patients (excluding women who refused treatment or were lost to follow-up) found that 25.6% (n=31) of the 121 remaining patients in the chemotherapy-only arm and 7.9% (n=11) of the 139 patients left in the triptorelin group experienced early menopause, a significant difference (P<.001). Triptorelin users resumed menstruation at a medium of 6.7 months after chemotherapy completion. Triptorelin did not appear to increase the rate of adverse events commonly associated with chemotherapy. Both study arms had similar numbers of recurrences and deaths. A subgroup analysis by HR status found women with HR-negative breast cancer far more likely to resume menstruation than women with HR-positive tumors, and triptorelin was associated with a more favorable outcome in both subgroups. Of the 22 HR-negative women assigned to chemotherapy alone, 74% resumed menstruation, as did 93% of HR-negative women who also took triptorelin. In addition, 44% of HR-positive women treated only with chemotherapy had resumption of menses compared with 55% of those also given triptorelin. The authors said studies with longer follow-up are needed to assess whether the positive effects of triptorelin and other GnRH analogues on ovarian function in younger women undergoing chemotherapy improve fertility rates. Although various methods of fertility preservation are available, the authors said some are complicated, whereas GnRH “does not require a male partner, is simple to administer, does not require delaying chemotherapy, and is less invasive and less expensive.” They noted that preserving ovarian function has other benefits, including prevention of vasomotor symptoms and sexual dysfunction.