In the first experience Forward et al. analyzed the endocrine effect and the efficacy of goserelin plus anastrozole. In the study were enrolled 16 premenopausal metastatic breast cancer patients who had progressed following therapy with goserelin and tamoxifen. The Authors reported that 75% of patients achieved objective response or stable disease at 6 months. Moreover the substitution of tamoxifen by anastrozole led to a 76% reduction in serum E2 levels compared to pretreatment. No patient discontinued the endocrine therapy because of toxicity.¹⁸

The combination of goserelin and anastrozole was further studied as first line therapy for metastatic premenopausal patients. In the study of Cheung et al. out of 36 patients enrolled, 67% achieved clinical benefit at 6 months and the median time to progression was 12 months. The combination of goserelin and anastrozole produced a drastic fall in median E2 level at 6 months compared to pretreatment. The therapy was well tolerated. Moreover, in a second step of the study, the Authors explored the clinical and endocrine data of further endocrine treatment with goserelin and steroidal AI (exemestane) following prior therapy with goserelin and tamoxifen or anastrozole. Out of 13 patients who fulfilled these criteria, 38% achieved a CB.¹⁹

Another phase II study looking at the first line use of goserelin and anastrozole in premenopausal advanced breast cancer was from Carlson et al. The Authors enrolled 35 patients. The CB was 72% and the median time to progression was 8.3 months. The E2 suppression level was assessed with mean E2 level of 18.7 pg/mL and 14.8 pg/mL at 3 and 6 months respectively.

No grade 4 or 5 of toxicities were reported, 59% of patients had flashes and 53% arthralgia.²⁰

The third study with similar design and comparable simple size was reported from a France group.

Roche et al. analyzed the efficacy of goserelin and anastrozole as first line therapy in 33 premenopausal advanced breast cancer patients. The CB was 64% and TTP of 13 months.²¹

More recently Nishimura et al. conducted a phase II study to assess the efficacy and tolerability of LHRH analogue and anastrozole after failure of standard LHRH analogue plus tamoxifen during adjuvant or metastatic setting. 37 pts were enrolled; the ORR was 18.9% and the CB 62.2%. Eight pts (21.6%) had adverse events, but none resulted in treatment.²²

The results reported by the studies mentioned above, focused on first line treatment, are essentially similar showing that the combination of goserelin and anastrozole is an effective therapy for metastatic premenopausal breast cancer patients with endocrine responsive disease.

On the other hand, the combination of goserelin and another AI, as letrozole, in premenopausal metastatic patients yielded clinical efficacy.

Yao et al. reported a retrospective analysis of the efficacy of LHRH analogue and letrozole in 52 premenopausal metastatic breast cancer, as first (n = 36) or second line (n = 16) hormonal therapy. The ORR and the CB were 21% and 71% respectively, the treatment was well tolerated.²³ In a prospective phase II study, Park et al. compared the clinical outcomes of 35 premenopausal metastatic patients received goserelin and letrozole to those achieved by letrozole alone in 38 postmenopausal metastatic patients. The hormonal treatment was given as first line in both groups of patients. The results were comparable between two groups, CB rate was 77% and 74% for premenopausal and postmenopausal patients respectively. The median TTP was 9.5 months for premenopausal group and 8.9 months for postmenopausal one, with no statistical difference.

The symptoms of hormone deprivation as dryness and flashes were more frequently reported in premenopausal patients while the protective effect of bisphosphonate therapy was observed in both groups.²⁴

Aromatase inhibitors and premenopausal breast cancer patients in neoadjuvant setting

Neoadjuvant therapy might be beneficial for patients with breast cancer in several ways beyond the possibility to achieve a breast conservation surgery in some of them. Moreover, the response to the neoadjuvant treatment may be utilized as a prognostic marker, since it has been showed to be associated with a longer disease-free survival (DFS) compared with no-response.²⁵

Literature data indicate that the pathological complete response (pCR) can be achieved only in a minority of patients with estrogen receptors (ER) positive disease, ranging from 2% to 10% of patients.^{[26] and [27]} In patients whose tumors express ER other primary end points, as ki-67 labelling index (Li) must be considered for evaluation of efficacy of neoadjuvant therapy.²⁸

As primary treatment, the AIs have shown to be effective and well tolerated treatments in postmenopausal women.⁸ While limited data are available on neoadjuvant treatments with AIs administered in premenopausal patients. Torrisi et al. analyzed the efficacy of letrozole in combination with LHRH analogues. The median duration of therapy was 5.2 months for letrozole. Thirty-two patients were considered evaluable for response. One patient (3%) obtained a complete clinical response, which was confirmed as a pCR at pathological examination. Fifteen patients (47%) obtained a partial response giving an ORR of 50%.²⁹ In another non-randomized study the concomitant use of LHRH analogue plus letrozole together with presurgical chemotherapy was effective in premenopausal women with locally advanced breast cancer in terms of improved disease-free survival.³⁰

A large phase III trial, the STAGE study, randomized 204 premenopausal women with ER positive, HER2-negative breast cancer to receive goserelin plus either anastrozole and tamoxifen placebo or tamoxifen and anastrozole placebo for 24 weeks before surgery. More patients in the anastrozole group had a complete or partial response than did those in the tamoxifen group during 24 weeks of neoadjuvant treatment (70.4% vs. 50.5%, respectively).³¹

Reduction in Ki67 index from baseline to week 24 was significantly greater with anastrozole vs. tamoxifen .Most adverse events were mild or moderate (grade 1 or 2). Treatment-related grade 3 adverse events were reported in two patients in the anastrozole group (arthralgia and syncope) and one patient in the tamoxifen group (depression). No events at grade 4 were recorded.

Aromatase inhibitors and premenopausal breast cancer patients in adjuvant setting

Tamoxifen alone or the combination of ovarian suppression and tamoxifen are the mainstay of adjuvant hormonal therapy in premenopausal women with endocrine-responsive breast cancer.³² The results of the randomized studies with the AIs in early postmenopausal breast cancer patients^{[9] and [10]} and the results in metastatic setting showing a more evident reduction in E2 levels with LHRH analogue combined with an AI as compared with ovarian suppression plus tamoxifen¹⁸ were the background to study the use of AIs and LHRH analogue as adjuvant therapy in premenopausal patients. Rossi et al. analyzed the endocrine changes that occur in premenopausal patients with early breast cancer after 6 months of hormonal therapy. Compared with OFS plus tamoxifen, the combination of letrozole and OFS induced a stronger suppression of median E2 while FSH levels were higher and LH levels were lower with letrozole than with tamoxifen. These results could be explained by a potent suppression of E2 levels produced by letrozole which removes the negative feedback of E2 on pituitary FSH secretion.¹²

In the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12), 1803 premenopausal patients with early breast cancer were assigned to receive goserelin plus tamoxifen or anastrozole with or without zoledronic acid for 3 years.³³ Updated results at 62 months revealed no difference in disease-free survival between patients on tamoxifen alone vs. anastrozole alone (HR 1.08, 95% CI 0.81–1.44; p = 0.591), but overall survival was worse with anastrozole than with tamoxifen (46 vs. 27 deaths; HR 1.75), possibly related to treatment administered after the relapse of the disease. The addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen.³⁴

Treatments were generally well tolerated. Women who received anastrozole alone, as compared with those who received tamoxifen alone, had higher incidences of arthralgia (19% vs. 8%) and bone pain (33% vs. 23%). Patients in the zoledronic acid groups had a higher incidence of bone pain, arthralgia, and pyrexia compared with the no zoledronic acid groups, no reports of renal failure or osteonecrosis of the jaw.

Two large phase III randomized clinical trials, coordinated by the International Breast Cancer Study Group (IBCSG) are addressing the value of AIs in combination with LHRH analogue as adjuvant therapy for premenopausal patients. The Tamoxifen and Exemestane Trial (TEXT) evaluates the role of exemestane plus LHRH analogue as adjuvant therapy for premenopausal women with endocrine responsive breast cancer 2639 patients have been included in the study and randomized to receive adjuvant Triptorelin for 5 years plus Tamoxifen for 5 years or Triptorelin for 5 years plus Exemestane for 5 years. In the Suppression of Ovarian Function Trial (SOFT) trial 3000 breast cancer patients have been randomized to receive adjuvant Tamoxifen for 5 years or OFS (triptorelin for 5 years or surgical oophorectomy or ovarian irradiation) plus Tamoxifen for 5 years or OFS plus Exemestane for 5 years. The results of these trials are expected in the coming years.

Discussion

The data from large randomized trials indicated that the AIs are more effective to tamoxifen in the treatment of postmenopausal patients. The data on the efficacy of AIs combined with OFS in premenopausal women are limited. Although limited, there are both endocrine and clinical data suggesting that AIs in combination with OFS might be of value in selected premenopausal women.

Generally the treatment with AIs in combination with OFS in premenopausal patients is well tolerated and few patients stopped the hormonal therapy due a serious adverse event.

The toxicities include the side effects due the estrogen deprivation; the short term adverse events more frequently reported include vaginal dryness, hot flashes, musculoskeletal pain and headache.

Fig. 1 and Fig. 2 show the comparison between the toxicities and the seriuos adverse events with AIs plus OFS vs. tamoxifen plus OFS in premenopausal patients in the studies of neoadjuvant and adjuvant setting respectively.

Generally the AI safety profile in premenopausal is the same already reported in postmenopausal setting, however the intensity of the side effects is frequently more evident with more significant impact on quality of life. Moreover, a field of research is to define long term toxicities of prolonged estrogen deprivation in young patients of potentially curative breast cancer treatments. The bone health is very important due the potentially long life expectation of young patients.

In postmenopausal patients data from large randomized studies reported that the use of AIs is associated with an increased risk of decline in bone mineral density and bone fracture compared with the tamoxifen therapy.

In a meta-analysis of seven trials comparing AIs to tamoxifen in postmenopausal women with early stage breast cancer, use of AIs significantly increased the risk of bone fractures (OR 1.47, 95% CI 1.34–1.61).³⁵

In the ABCSG 12 trial 404 premenopausal patients were prospectively included in the bone sub study. Significant bone loss was reported at the lumbar spine after 3 years of ovarian suppression plus tamoxifen or anastrozole and bone loss was more severe in patients who were assigned anastrozole compared with those assigned tamoxifen. Even if there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline bone mineral density (BMD) levels. By contrast the concomitant zoledronic acid therapy prevented bone loss during hormonal therapy and improved BMD at 5 years.³⁶

However the use of bisphosphonates in premenopausal patients remains to be tested in further clinical trials.

Another important issue is the potential detrimental effect on prolonged estrogen deprivation on cognitive function. Preclinical data support that estrogens have neurotrophic and neuroprotective actions in the brain improving cognitive function by promoting cholinergic activity in the brain.³⁷ The estrogens in fact could be involved in maintaining and regulating neuronal circuitry in several brain regions known to be important in cognition. Thus, it is theoretically plausible that endocrine therapies for breast cancer, aiming at estrogen deprivation, might influence brain activities. Data on postmenopausal patients taking AIs are not conclusive. The postmenopausal breast cancer patients taking adjuvant letrozole during the fifth year of treatment have better cognitive function than those taking tamoxifen, suggesting aromatase inhibitors do not adversely impact cognition compared with tamoxifen.³⁸ On the other hand recently data support an improvement in cognitive function after cessation of hormonal therapy.³⁹

For premenopausal patients in the ABCSG B12, 0.7% and 0.9% of patients taking anastrozole (in combination with OFS) and tamoxifen (in combination with OFS) respectively showed a cognitive disorders but no data are available on the long term use of AIs on the cognitive effect in premenopausal women. This field requires future researches.

In conclusion, given the available evidence at the time new studies are required to confirm the role of OFS plus an AI in premenopausal women.

In metastatic setting for premenopausal patients suitable of endocrine therapy, OFS combined with additional endocrine therapy is the treatment of choice. The additional endocrine agent should be tamoxifen unless tamoxifen resistance is proven. An AI is a viable option, if tamoxifen resistance is proven, although mandates the use of OFS.¹⁴ In neoadjuvant setting the AIs in combination of LHRH analogue should not be used outside of a clinical trial.

In the adjuvant setting, tamoxifen alone or OFS plus tamoxifen are reasonable options. Despite the lack of conclusive data favoring the combination of tamoxifen plus OFS, this treatment might be a reasonable option for subgroups of patients such as very young patients, OFS alone should nort be considered unless tamoxifen was contraindicated.³³

Similarly, in cases where tamoxifen is contraindicated, AIs as an adjunct to OFS is a treatment option in premenopausal patients.

Conflict of interest

The authors declare no conflicts of interest.

References