Fertility Preservation in Breast Cancer: Use of GnRH Agonists

Comprehensive insight to available gonadotropin-releasing hormone (GnRH) agonists in breast cancer and the role they play when thinking about fertility preservation.


Virginia G. Kaklamani, MD, DSc: When you use the GnRH [gonadotropin-releasing hormone] agonist to preserve fertility during chemotherapy, there [are] three that we typically use. Is there a differentiation between which one to consider, and do you use that monthly…every 3 months? What is your process?

Matteo Lambertini, MD, PhD:In my practice, I don’t have a special preference [for] one of the 3 different options that we have. I usually try to do what the clinical trials have done in this setting. We have run [one such] trial, the PROMISE-GIM6 study in Italy, so we have the tendency of going in the direction of this trial. This trial, but also the other randomized studies that have evaluated the use of GnRH agonist during chemotherapy, have all included the monthly administration. In my practice, I use the 28-day administration with this regimen and I tend to start at least 1 week before initiating chemotherapy, as was done in these studies…. [T]his is not always possible, so I may go a bit closer to the start of chemotherapy, but the preference is to start at least 1 week before initiating chemotherapy with a monthly administration. There is a prospective study from Korea that has tried to investigate the difference between two of the different GnRH agonists; not a randomized trial, but still a prospective core study that has seen similar results in terms of ovarian protection during chemotherapy. So again, I will not have a strong preference for one of the different options, but between the monthly or the 3-month administration, so far I will still go for the monthly administration. Of course, this could be partially different if we discuss ovarian suppression as adjuvant endocrine therapy like as per SOFT [Suppression of Ovarian Function Trial] and TEXT [Tamoxifen and Exemestane Trial design. Then we may discuss different ways of administration and timing between the different doses, but still also in the adjuvant setting and particularly when I combine an aromatase inhibitor where I really need to have a complete ovarian suppression, so far I go for the monthly administration. There is an important study ongoing and this study is trying to investigate the ovarian suppression potential of the 3-month administration in the adjuvant setting as part of adjuvant endocrine therapy. So far a patient will be still more comfortable to discuss the monthly administration. So, I don’t know, Virginia, what you think on that, not only during chemotherapy, but also as adjuvant endocrine therapy; what’s your approach with our premenopausal patient?

Virginia G. Kaklamani, MD, DSc: I do the same thing. I think the monthly administration, as you mentioned, has been studied more. I’ve seen several, especially younger women with a 3-month administration that at around 2½ or so months, they will tell you they’re starting to have symptoms of wanting to menstruate. That…tells me that they’re not being suppressed for all 3 of those months. And when we start talking about adjuvant therapy with an aromatase inhibitor where it’s important that they are suppressed constantly, it tends to be a little tricky. But this is, again, where we need data and we need to know, should we be checking estradiol levels, should we be checking FSH [follicle-stimulating hormone], or should we just rely on the GnRH agonist to do its job? And we know in some of the studies that did that there was not as full suppression as what we wanted this to be. Maybe for oncofertility that may not be as important, but when we start talking about treatment for these women, I think this is extremely important.

Matteo Lambertini, MD, PhD:We have several randomized clinical trials that have investigated the efficacy of using a GnRH agonist during chemotherapy to reduce ovarian functions of chemotherapy-induced premature ovarian insufficiency in premenopausal women [with] breast cancer. These trials have used different formulation of GnRH agonists, but all of them have used a month administration with indication to start a GnRH agonist during chemotherapy at least 1 week before initiating chemotherapy. Of course cross-trial comparison is difficult, but what I can say with the largest studies like the OPTION study, the POEMS, the PROMISE-GIM6 trials that have used different GnRH agonists where if we do a cross-trial comparison, we see very similar results in terms of reducing the risk of premature ovarian sufficiency. So, they are menorrheal following chemotherapy. Two of these trials have also investigated the long-term outcomes, in particular the pregnancies. Both of them have seen a tendency for a higher number of pregnancies in those women [who] receive GnRH agonists during chemotherapy as compared [with] those patients that receive chemotherapy alone. In 2018 there was an individual patient-level meta-analysis published in JCO [Journal of Clinical Oncology]that pooled the results from these major trials. The results are the same: significant reduction in the risk of premature ovarian insufficiency, around 15% absolute reduction in the incidence of chemotherapy-induced amenorrhea, and a significant improvement in pregnancy rates with a doubling in the number of pregnancies for those patients [who] received GnRH agonists during chemotherapy. In terms of pregnancies now, they are still small, but the results were significantly in favor of the use of GnRH agonists during chemotherapy.

Transcript edited for clarity.

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