In order to evaluate the safest strategy to preserve fertility, two major trials have been conducted in breast cancer patients in the last years. The Prevention of Early Menopause Study (POEMS-SWOG)73showed that temporary ovarian suppression with goserelin during chemotherapy was associated with a significant reduction in the risk of treatment-related POF (8 vs 22%; OR 0.30; 95% CI 0.09–0.97) (Table 3). The updated results presented at San Antonio Breast Cancer Symposium (SABCS) 2017 after a median follow-up of 5.1 years showed higher pregnancy rates in the goserelin group compared with those in the standard group (22 vs 12%; OR 2.38; 95% CI 1.08–5.26, P=0.05); this has been associated with improved survival with a significant increase in both DFS and OS in the LHRH analog containing group.89 The second one is the Italian Study (PROMISE-GIM6) conducted by Del Mastro et al71 which showed a significant protective effect with the use of LHRH analog triptorelin in preserving ovarian function 1 year after the end of chemotherapy (9 vs 26%; OR 0.28; 95% CI 0.14–0.59) and also at long-term follow-up (Table 3). Furthermore, an increased pregnancy rate was reported by both the studies.71,73 This information was confirmed in a meta-analysis published in 2015 that included 12 randomized studies: the use of GHRH analogs was associated with a significant reduced risk of POF (OR 0.36; P<0.001) and a significantly increased number of pregnancies (33 vs 19 women; OR 1.83; P=0.041) with no apparent negative impact on patients’ prognosis (Table 3).90 This finding seems to conclude the long debate behind the pharmacological protection for fertility preservation and in the light of this evidence; the last version of Italian guidelines regarding the issue of fertility recommends this strategy in all premenopausal patients undergoing chemotherapy.87


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(To view a larger version of Table 3, click here.)

There is no complete agreement on the role of LHRH analogs on the preservation of fertility, according to the second international consensus guidelines for breast cancer in young women (BCY2).85 While in the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer91 and in National Comprehensive Cancer Network (NCCN) guidelines,83 this strategy should be discussed with the patients; in the American Society of Clinical Oncology (ASCO)86 and European Society for Medical Oncology (ESMO)84 guidelines, the use of LHRH during chemotherapy is not recommended because it is considered as an experimental technique. The major reason for this difference is probably that the latest version of ASCO and ESMO guidelines were published in 2013 and an update is needed to encompass this new information.84,86 The recent result of the Phase III study (OPTION92) has shown that the use of LHRH analog (goserelin) provides some protection to the ovarian function during chemotherapy in women younger than 40 years. The effect seems to be uncertain for women who are older than 40 years (≤40 amenorrhea: 10 vs 25.4%, P=0.032, premature ovarian insufficiency (POI): 2.6 vs 20%, P=0.038; >40 amenorrhea: 42.9 vs 54.2%,P=0.376, POI: 42.3 vs 47.2%, P=0.798).92 These results are in the same direction of two other studies and a meta-analysis. The results of the meta-analysis from five randomized clinical trials (PROMISE-GIM6,71 POEMS/SWOG,73 OPTION,92 GBG 37 ZORO,93 and Moffitt Cancer Center-led trial94), in which premenopausal women with early breast cancer (EBC) were randomized to receive chemotherapy alone or with LHRH (437 or 436 women, respectively), have been recently presented by the Lambertini et al at the SABCC 2017. The POI rate was 14.1% in the LHRH group and 30.9% in the control group (adjusted OR 0.38; 95% CI 0.26–0.57; P<0.001), and the post-treatment pregnancy rate was 37 in the LHRH group vs 20 in the control group (incidence rate ratio 1.83; 95% CI 1.06–3.15; P=0.030). Similar DFS and OS were observed between groups regardless of the ER status.95 According to some of the principal authors in this field, the puzzle on the protective role of temporary ovarian suppression with LHRH analogs during chemotherapy has been completed.96

CONCLUSION

After several years of debate and studies, the role of LHRH analogs appears more definite to the adjuvant treatment of premenopausal women with endocrine-sensitive breast cancer. First, the adjuvant trials (TEXT/SOFT) point out the adequate length of LHRH treatment in the premenopausal setting and delineate the class of risk in which LHRH appears more beneficial; 5 years of LHRH treatment is an adequate treatment length in the high-risk setting, whereas it is not beneficial in the low-risk subset. The role of LHRH was also explored in the preservation of the ovarian function allowing the oncologist the possibility of offering a safe and effective treatment together with the other existing fertility preservation techniques. Triptorelin represents one of the LHRH analogs available in clinical practice worldwide; it has been extensively studied in various trials that have confirmed the magnitude of its effectiveness in the adjuvant treatment of early breast cancer in the premenopausal setting and represents a safe and successful treatment.

Acknowledgments

This review has been conducted following the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The objective of this review was to specifically evaluate the role of LHRH analog triptorelin in the management of early breast cancer. The types of studies selected in this review were as follows: randomized controlled clinical trials and their related updates, meta-analyses, and relevant published studies concerning the role of triptorelin in the breast cancer treatment. Also, the published trials and their related updates, concerning the role of triptorelin, and other LHRH analogs were selected to evaluate its role in the preservation of ovarian function in the early breast cancer setting.

Author contributions

All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.


Marta Venturelli,1 Giorgia Guaitoli,1 Claudia Omarini,1 Luca Moscetti2

1Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy; 2Division of Medical Oncology, Department of Oncology and Hematology, Azienda Ospedaliero Universitaria Policlinico di Modena, Modena, Italy 


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Source: Breast Cancer: Targets and Therapy.
Originally published March 6, 2018.