Fertility preservation, its effectiveness and its impact on disease status in pre-menopausal women with breast cancer: A systematic review and meta-analysis

Abstract

Introduction

Preservation of reproductive function is a key concern for many premenopausal women with breast cancer, given the known gonadotoxic effects of treatments. The present systematic review aimed to investigate the effectiveness and safety of fertility preservation strategies in pre-menopausal women with breast cancer.

Methods

Primary research assessing fertility preservation strategies of any type was identified. Markers of preservation of fertility including return of menstrual function, clinical pregnancy rates and live birth rates were selected as main outcome measures. An additional analysis of safety data was also performed.

Results

Fertility preservation interventions were overall associated with higher fertility outcomes: with a pooled odds ratio 4.14 (95% CI 3.59–4.77) for any kind of fertility preservation intervention. This was seen both for return of menstruation and for clinical pregnancy rate, but not for live birth rates. Fertility preservation was associated with a reduced rate of disease recurrence (OR 0.63 (95% CI 0.49–0.81)), while there was no significant difference in disease free survival (OR 0.88 (95% CI 0.74–1.05)) or in overall survival (OR 0.9 (95% CI 0.74–1.10)) between the fertility preservation group and those who had not undergone fertility preservation.

Conclusion

Fertility preservation is both effective in preserving reproductive function, and safe with regard to disease recurrence, disease free survival and overall survival in premenopausal women with breast cancer.

Introduction

Breast cancer is the most common cancer in women worldwide, as well as the most common cancer in women of childbearing age [1]. This is particularly problematic due to the known impact of breast cancer treatments on fertility; current chemotherapeutic agents are known to be associated with amenorrhoea [2] and diminished ovarian reserve [3].

Treatment related subfertility is associated with psychosocial stress in cancer patients [4]. Concerns about future fertility also have potential repercussions for treatment related decisions [5] and are associated with poorer regime adherence [6]. The European Society for Medical Oncology (ESMO) recommends women desiring pregnancy should be counselled about fertility preservation options soon after a cancer diagnosis [7]. Embryo or oocyte cryopreservation are standard strategies for fertility preservation in female patients, requiring ovarian stimulation before the commencement of chemotherapy [7]. More recently, other largely experimental, fertility preservation strategies such as cryopreservation of ovarian tissue, and ovarian suppression with gonadotropin-releasing hormone (GnRH) agonists have been developed [8]. GnRH agonist/antagonists are given prior to chemotherapy administration, in order to supress ovarian function during chemotherapy, with the aim of protecting the ovary from the effects of chemotherapy [8].

Despite the wide range of fertility preservation options available, evidence recommending these interventions is currently limited. In 2010, a systematic review was conducted of research into fertility preservation strategies used by premenopausal women exposed to adjuvant chemotherapy for breast cancer [9]. At the time there were no randomised controlled trials addressing the effectiveness of fertility preservation, however there were four that were ongoing. This lack of evidence demonstrates a need for a subsequent, updated systematic review encompassing previous and recently published evidence for the relative effectiveness of different fertility preservation techniques.

There are also concerns on the safety of utilising fertility preservation strategies. These include whether fertility preservation necessitates a delay in treatment initiation, however evidence suggests this is not the case [10]. The fertility preservation strategies generally require controlled ovarian stimulation resulting in supraphysiological serum estradiol levels presenting a possible risk for women with hormone-sensitive breast cancers. Clinical studies indicate that fertility preservation with oocyte or embryo cryopreservation is safe, as assessed by no change in disease free survival [11]. Given the seriousness of these risks there is a need for further evaluation of the safety of fertility preservation techniques, using a larger patient population.

The current systematic review and meta-analysis will evaluate the effectiveness of all types of fertility preservation strategies on fertility outcomes in pre-menopausal women with breast cancer, using both direct and surrogate measures of fertility preservation: return of menstrual function, clinical pregnancy rates and live birth rates. A secondary goal of this review is to evaluate the extent to which fertility preservation may increase the likelihood of disease recurrence, disease free survival or overall survival.