Reviews in Oncology Reviews in Oncology CIC Edizioni Internationali 2013 January-March; 1(1): 29–32. ISSN: 2282-6378

Adjuvant hormone therapy in early breast cancer: aromatase inhibitors and the perimenopausal status

Luca Moscetti, Fabrizio Nelli, and Enzo Maria Ruggeri

UOC of Oncology, Ospedale Belcolle, AUSL Viterbo, Viterbo, Italy

AIs are classified as steroidal (irreversible, type I) and nonsteroidal (reversible, type II). The currently AIs available are represented by the steroidal AI exemestane and the nonsteroidal AIs anastrozole and letrozole (4, 5). These agents determine a deep suppression of the 98% of the circulating estrogens (69). The role of AIs is not clear in the adjuvant setting of the perimenopausal status and for women who are premenopausal at diagnosis and appear to have a cessation of menses after adjuvant chemotherapy. The clear definition of meno-pausal status is essential for all of the patients undergoing a hormone therapy. The World Health Organization (WHO) defines the menopause as follow: menopause is the permanent cessation of menstruation that results from loss of ovarian follicular activity. The perimeno-pause corresponds to the period before the menopause and at least to the first year after the menopause. The post-menopause dates from the menopause, although it cannot be definitively determined until a period of 12 months of spontaneous amenorrhea has occurred (10). According to the WHO definition, the perimenopause could be restricted only to a one year period but this definition cannot be strictly applied to women with a chemotherapy-induced amenorrhea because of the likelihood menses resumption ranges from 4 to 29 months (11). The National Comprehensive Cancer Network (NCCN) guidelines define the menopause as follow: prior bilateral oophorectomy, age >60 years, age ≤60 years and amenorrhea for at least 12 months in absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, or age ≤60 years and FSH and estradiol in the postmenopausal range in case of therapy with tamoxifen or toremifene (12). With regard of the definition of menopause for the use of AIs in randomized trials, the five available clinical studies don’t help us to find a explicit description (Tab. 1). The lack of menses induced from chemotherapy in a premenopausal woman, even induced 5 years before, is not a certainty of a real menopausal status. The serial monitoring of serum estradiol, FSH and LH currently represent the only standardized method to determine the menopausal status. New markers are now developing as reported by Anders et al. (13). These authors investigated the role of inhibin B and anti-Müllerian hormone and reported that the risk of chemotherapy related amenorrhea increased among women with lower pre-chemotherapy Inhibin B (RR = 1.67, p = 0.15) and anti-Müllerian hormone (AMH) (RR = 1.83, p = 0.05). Among patients whose prechemotherapy Inhibin B and AMH values were below the median, the incidence of CRA was 87.5%. These results indicate that prechemotherapy Inhibin B and AMH are lower among women experiencing CRA and may be predictive of CRA among premenopausal women undergoing chemotherapy for early stage breast cancer.

Table 1 Table 1
Definition of menopause in the main clinical trials of aromatase inhibitors in adjuvant treatment of early breast cancer.

In the postmenopause the serum estrogen levels are maintained at a modest steady state through the conversion of androgen into estrogen by the aromatase enzyme. The inhibition of estrogen levels, as the result of the aromatase-induced block, could stimulate an increase of the gonadotropin release, which could in turn stimulate the ovarian production of estrogen. The absence of menses after chemotherapy does not translate in absence of ovarian function and premenopausal consistent levels of estradiol were found in some women with chemotherapy-induced amenorrhea (14). In healthy premenopausal women an estradiol suppression has been observed with the use of anastrozole as a single agent (15). The resultant of this action is the increase in serum of gonadotropin levels which stimulate follicular growth and estradiol production through a mechanism of feedback. The use of an AI for induction of ovulation, such as letrozole, at the standard dose 2.5 mg per day, was explored and has been shown to induce an effective ovulation (16). Hargis et al. reported the case of a 40 years old woman who presented, after five years of tamoxifen, the resumption of menses soon after the initiation of letrozole. Several similar cases are reported in literature and, taken together, these reports point out the substantial biologic differences in the pre- and postmenopausal status (3, 4). Smith et al. reported the effects of treatment with AIs in 45 premenopausal women who became amenorrheic after chemotherapy. The median age was 47 years (range 39 to 52) and 33 had biochemically confirmed ovarian suppression before starting treatment. Eighteen (40%) had the recovery of ovarian function with 1 patient becoming pregnant without prior menstruation, whereas eight patients had the recovery of ovarian function, which was biochemical confirmed, with a median plasma estradiol of 252 pmol/L (range, 47 to 461 pmol/L). Twenty-four of the remaining 33 patients (73%), who remained clinically postmenopausal, also had a biochemical ovarian function check and all of them maintained postmenopausal plasma estradiol levels (17).

Preliminary experiences in the metastatic settings showed the feasibility of combining LHRH agonists and AIs (Tab. 2) (1822) and the Hoboe trial currently explores the role of this association in the adjuvant treatment of premenopausal women (23). The preliminary results showed that letrozole in combination with triptorelin induced a more intense suppression of estradiol levels compared to the tamoxifen group. In both groups of patients FSH and LH levels were suppressed but FSH levels were higher and LH levels were lower with letrozole than with tamoxifen. These effects may be due to the potent suppression of E2 levels produced by letrozole. There are no other data supporting the use of an AI in combination with LHRH agonists but two large, ongoing, randomized trials are addressing the value of AIs in premenopausal women (24, 25).

Table 2 Table 2
Association of LHRH and AIs in the metastatic settings.

The trial by Gnant et al. explored the endocrine treatment in combination with zoledronic acid in the premenopausal setting. No differences emerged between tamoxifen and anastrozole and the trial generates hypothesis to test the association of LHRH agonists and anastrozole in the adjuvant setting but no data are available on the endocrine safety (26).

The recent update of the trial shows similar disease free survival between anastrozole and tamoxifen, but patients treated with tamoxifen had significantly higher overall survival compared to anastrozole (27).

An update of the MA 17 trial showed that the efficacy of AIs in women who are premenopausal at diagnosis and become menopausal during tamoxifen, is more pronounced than postmenopausal women, but no data are available on safety in this subset population (28).

AIs represent the standard of care for adjuvant hormone therapy of postmenopausal women with early breast cancer and current guidelines recommend its use as up-front therapy, as switching strategy after 2–3 years of tamoxifen, or as extended treatment after 5 years of tamoxifen. In premenopausal women tamoxifen represents the drug of choice with or without the association of LHRH agonists. Owing to the potential of ovary stimulation and probability of resumption menses, AIs should no to be offered in this setting. The women who became amenorrheic after chemotherapy should not be considered postmenopausal. The cessation of menses is not synonymous of true ovarian failure because the estrogens levels can remain in a premenopausal range in spite of one year or longer of chemotherapy-induced amenorrhea and the AIs might determine the resumption of ovarian function. The monitoring of estradiol, FSH and LH values should be performed before prescribing an AI. In summary women aged younger than 40 years should not receive an AIs and perimenopausal women who developed chemotherapy-induced amenorrhea should be offered tamoxifen as the preferable option. The role of AIs is defined in the postmenopause, the results of the large ongoing clinical trials will address the issue in the pre- and perimenopausal setting.