The case for aromatase inhibitors use in Oncofertility patients. Should aromatase inhibitors be combined with gonadotropin treatment in Breast Cancer patients undergoing ovarian stimulation for fertility preservation prior to chemotherapy? A debate

Abstract

Breast cancer is one of the hormone-dependent cancers that may be adversely affected by elevated oestrogen or progesterone concentrations, particularly the endocrine active (hormone receptor positive) breast cancers. Treatment for breast cancer patients aimed at fertility preservation, includes ovarian hyperstimulation, the harvest of oocytes, and subsequent cryopreservation of oocytes or embryos. Classically, gonadotrophins have been used effectively for ovulation induction, a treatment often accompanied by high blood oestrogen concentrations produced by the hyperstimulated granulosa cells. Despite the uncertainty which surrounds this issue and the lack of clear-cut clinical evidence, it is still of major concern that these ensuing high hormone levels might be associated with a high risk of recurrence of the cancer. A growing number of clinical studies have strongly suggested the benefits of using aromatase inhibitors in infertility treatment, both as single agents or as adjuncts to FSH-containing ovulation induction regimes in reproductive medicine. Combining gonadotrophins with aromatase inhibitors would augment the stimulation effect, with a reduced increase in serum concentrations of estradiol. We propose to open a debate over the use of aromatase inhibitors in combination with FSH in ovulation induction treatment of breast cancer oncofertility patients. As the safety of aromatase inhibitors such as letrozole has recently been demonstrated in several studies, and there is growing concern over the possible detrimental effects of high estradiol levels on breast cancer cells (at least in mouse models), the co-administration of letrozole in these patients would reduce both the high supraphysiologic serum levels of estradiol and the intratumoral in situ production of oestrogen. However, since it is unlikely that a well-founded evidence-based justification of this treatment will be formulated in the near future, based on well-designed prospective randomised controlled trials, we advocate a wider use of aromatase inhibitors in combination with gonadotrophins in breast cancer patients, especially those with hormone-receptor-positive tumours.

Fertility preservation for women with breast cancer before chemotherapy: a systematic review and meta-analysis

“…Lower estradiol level achieved by letrozole co-treatment may potentially confer lower risk to the patient; whether it translates to better prognosis of the patients' cancer disease would require further investigation. Current studies have echoed that letrozole is both safe in terms of obstetric outcomes and decreasing estradiol levels during stimulation (Fatum et al, 2013). Concurrently, a meta-analysis concluded that letrozole does not have a negative effect on the number of mature oocytes retrieved while suggesting a benefit of decreasing peak estradiol levels in patients and same stimulation length as hormone-sensitive cancers, signifying the safety of this protocol (Bonardi et al, 2020).…”

Ovarian response to controlled ovarian hyperstimulation in women with cancer is as expected according to an age-specific nomogram

“…A potential increase of the gonadotrophin effect due to the use of aromatase inhibitors cannot be ruled out [17].…”

Preserving fertility in female patients with hematological malignancies: a multidisciplinary oncofertility approach

“…It is also not suitable in case of estrogen-sensitive cancers, such as breast and endometrial cancers as conventional ovarian stimulation may lead to high serum estrogen levels. For such cases, alternative ovarian stimulation protocols with either tamoxifen (selective estrogen receptor modulator) [51,52] or letrozole (aromatase inhibitor) [53][54][55][56][57][58] may be used. In addition, conventional ovarian stimulation may take up to several weeks and, in some cases, it may complicate into ovarian hyperstimulation syndrome making it not suitable for women with highly aggressive malignancies that require immediate anticancer treatment such as leukemia.…”