Factors associated with ovarian function recovery after chemotherapy for breast cancer: a systematic review and meta-analysis.
Which factors related to patient, treatment or disease are associated with ovarian function recovery after chemotherapy in premenopausal women with breast cancer?



Younger age and GnRH agonist (GnRHa) administration during chemotherapy were significantly associated with menses recovery, but this recovery was less likely in patients exposed to taxanes.



To date, published meta-analyses have only assessed GnRHa administration as a possible factor for ovarian function recovery, and their results were conflicting. Current guidelines present distinct recommendations regarding the use of GnRHa for fertility preservation (FP) in women with breast cancer.



A systematic review and meta-analysis of published studies in the English, Portuguese, French or Spanish languages (1990-2015), ongoing trials or completed trials (1990-2015) and conference proceedings (2000-2015) were performed.



We searched the MEDLINE, Embase, LILACS, Scielo, Toxline and DART databases, online trial registries and conference proceedings. Studies were eligible if they included premenopausal women with early breast cancer treated with chemotherapy, reported ovarian function recovery data and identified factor(s) associated with recovery. Two authors independently screened the studies, extracted data and assessed the risk of bias. An odds ratio (OR) was estimated from the number of recovery events. A meta-analysis was conducted using a random-effects model.



Fifteen articles were included. Five different factors were analysed: younger age and baseline levels of anti-Müllerian hormone (patient-related factors), co-administration of GnRHa, addition of taxanes to anthracycline-based chemotherapy and addition of endocrine therapy to chemotherapy (treatment-related factors). Menses recovery was the most used marker. Younger age (≤40 years) and exposure to GnRHa were positively associated with menses recovery (OR 6.07 and 2.03, respectively) but exposure to taxanes adversely affected recovery (OR 0.49). Significant heterogeneity among studies was found.



A general limitation of the included studies is the use of menses as the main recovery marker. Regarding GnRHa, the substantial heterogeneity and conflicting results limit the interpretation of our results. Studies that use additional markers and have a longer follow-up are needed.



The decision for using chemotherapy regimens with taxanes must take into account their potential adverse effects on female fertility. Considering the conflicting results regarding GnRHa agonist use, other fertility preservation strategies should also be considered.



No external funding was received. There are no conflicts of interest to declare.



This review was registered at PROSPERO (CRD42015013494).
Centre for 20th Century Interdisciplinary Studies-CEIS20, Faculty of Pharmacy of the University of Coimbra, Rua Filipe Simões n° 33, 3000-186 Coimbra, Portugal tina.silva@sapo.pt.
Cristina
C
Silva
Gynecology Department, Coimbra Hospital and University Centre (CHUC), EPE, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal.
Olga
O
Caramelo
Centre for Fertility Preservation, Human Reproduction Department, Coimbra Hospital and University Centre (CHUC), EPE, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal.|Faculty of Medicine of the University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.
Teresa
T
Almeida-Santos
Centre for 20th Century Interdisciplinary Studies-CEIS20, Faculty of Pharmacy of the University of Coimbra, Rua Filipe Simões n° 33, 3000-186 Coimbra, Portugal.|Pharmacy Department, Coimbra Hospital and University Centre (CHUC), EPE, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal.
Ana Cristina
AC
Ribeiro Rama
D000367:Age Factors; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D005260:Female; D059247:Fertility Preservation / Q000379:methods; D006801:Humans; D010053:Ovary / Q000187:drug effects*; D020127:Recovery of Function / Q000187:drug effects*
D000970:Antineoplastic Agents
GnRH agonists, chemotherapy; antineoplastic agents; breast cancer; fertility; fertility preservation; ovarian function; recovery factors