Ovarian stimulation for oocyte vitrification does not modify disease-free survival and overall survival rates in patients with early breast cancer


      Research question

      Does ovarian stimulation for oocyte vitrification affect disease-free survival and overall survival rates in women with early breast cancer?


      This cohort study included 259 patients with early breast cancer; 148 patients underwent ovarian stimulation, whereas 111 patients did not. Patients were treated between January 2008 and December 2016. To calculate the disease-free survival time and overall survival rate, the time of definitive surgery was defined as the starting point. The follow-up was conducted up to 5 years.


      Exposed and non-exposed groups were comparable in tumour, node and metastases classification, Nottingham grade, hormonal receptor status, tumour molecular phenotype, histology and pathology stage. The exposed group was younger than the non-exposed. Recurrences occurred in 9/148 women (6.1%) in the exposed group and 15/111 women (13.5%) in the non-exposed group, with no significant difference. The mean disease-free survival time was 63.9 months (95% confidence interval [CI]: 61.5–66.4) in the exposed group and 60.6 months (95% CI: 56.9–64.2) in the non-exposed, with no significant difference (log-rank [Mantel–Cox] test). Overall survival rates were comparable; 2/148 (1.4%) and 4/111 (3.6%) patients died, in exposed and non-exposed groups, respectively, during the period analysed. Mean overall survival times were 67.2 months (95% CI: 66.2–68.2) in the exposed group and 65.9 months (95% CI: 64.0–67.9) in the unexposed, with no significant difference (log-rank [Mantel–Cox] test).


      This study suggests that ovarian stimulation in patients with early-stage breast cancer is safe in the long term.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Reproductive BioMedicine Online
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Altobelli E.
        • Rapacchietta L.
        • Angeletti P.M.
        • Barbante L.
        • Profeta F.V.
        • Fagnano R.
        Breast Cancer Screening Programmes across the WHO European Region: Differences among Countries Based on National Income Level.
        Int. J. Environ. Res. Public Health. 2017; 14
        • Alviggi G.
        • Marci R.
        • Vallone R.
        • Conforti A.
        • Di Rella F.
        • Strina I.
        • Picarelli S.
        • De Rosa P.
        • De Laurentiis M.
        • Yding Andersen C.
        High progesterone levels during the luteal phase related to the use of an aromatase inhibitor in breast cancer patients.
        Eur. Rev. Med. Pharmacol. Sci. 2017; 21: 3134-3138
        • Azim A.A.
        • Costantini-Ferrando M.
        • Oktay K.
        Safety of fertility preservation by ovarian stimulation with letrozole and gonadotrophins in patients with breast cancer: a prospective controlled study.
        J. Clin. Oncol. 2008; 26: 2630-2635
        • Boukaidi S.
        • Cooley A.
        • Hardy A.
        • Matthews L.
        • Zelivianski S.
        • Jeruss J.
        Impact of infertility regimens on breast cancer cells: follicle-stimulating and luteinizing hormone lack a direct effect on breast cell proliferationin vitro.
        Fertil. Steril. 2012; 97: 440-444
        • Brinton L.A.
        • Scoccia B.
        • Moghissi K.S.
        • Westhoff C.L.
        • Althuis M.D.
        • Mabie J.E.
        • Lamb E.J.
        Breast cancer risk associated with ovulation-stimulating drugs.
        Hum. Reprod. 2004; 19: 2005-2013
        • Chung K.
        • Hovanessian-Larsen L.J.
        • Hawes D.
        • Taylor D.
        • Downey S.
        • Spicer D.V.
        • Stanczyk F.Z.
        • Patel S.
        • Anderson AR.
        • Pike M.C.
        Breast epithelial cell proliferation is markedly increased with short-term high levels of endogenous oestrogen secondary to controlled ovarian hyperstimulation.
        Breast Cancer Res. Treat. 2012; 132: 653-660
        • Cobo A.
        • Serra V.
        • Garrido N.
        • Olmo I.
        • Pellicer A.
        • Remohí J.
        Obstetric and perinatal outcome of babies born from vitrified oocytes.
        Fertil. Steril. 2014; 102: 1006-1015
        • Criscitiello C.
        • Golshan M.
        • Barry W.T.
        • Viale G.
        • Wong S.
        • Santangelo M.
        • Curigliano G.
        Impact of neoadjuvant chemotherapy and pathological complete response on eligibility for breast-conserving surgery in patients with early breast cancer: A meta-analysis.
        Eur. J. Cancer. 2018; 97: 1-6
        • Daum H.
        • Peretz T.
        • Laufer N.
        BRCA mutations and reproduction.
        Fertil. Steril. 2018; 109: 33-38
        • Diaz-Garcia C.
        • Domingo J.
        • Garcia-Velasco J.A.
        • Herraiz S.
        • Mirabet V.
        • Iniesta I.
        • Cobo A.
        • Remohí J.
        • Pellicer A.
        Oocyte vitrification versus ovarian cortex transplantation in fertility preservation for adult women undergoing gonadotoxic treatments: a prospective cohort study.
        Fertil. Steril. 2018; 109: 478-485
        • Doménech JM
        Fundamentos de Diseño y estadística. UD 4: Descripción de datos de supervivencia.
        Signo, Barcelona2006
      1. Domingo, J., González S. Aumento del oestradiol durante la estimulación ovárica en la paciente con cáncer de mama. ¿Es realmente deletéreo? 32 Congreso Nacional de la Sociedad Española de Fertilidad. 16–18 May 2018. Madrid.

        • Domingo J.
        • Guillem V.
        • Ayllón Y.
        • Martínez M.
        • Muñoz E.
        • Pellicer A.
        • Garcia-Velasco J.A.
        Ovarian response to controlled hyperstimulation in cancer patients is diminished even before oncological treatment.
        Fertil. Steril. 2012; 97: 930-934
        • Doyle P.
        • Maconochie N.
        • Beral V.
        • Swerdlow A.J.
        • Tan SL.
        Cancer incidence following treatment for infertility at a clinic in the UK.
        Hum. Reprod. 2002; 17: 2209-2213
        • Garcia-Velasco J.A.
        • Domingo J.
        • Cobo A.
        • Martínez M.
        • Carmona L.
        • Pellicer A.
        Five years’ experience using oocyte vitrification to preserve fertility for medical and nonmedical indications.
        Fertil. Steril. 2013; 99: 1994-1999
        • Garcia-Velasco J.A.
        Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos.
        Fertil. Steril. 2012; 97: 527-528
        • Han H.J.
        • Heo J.S.
        • Lee Y.J.
        oestradiol-17b stimulates proliferation of mouse embryonic stem cells: involvement of MAPKs and CDKs as well as protooncogenes.
        Am. J. Physiol. Cell. Physiol. 2006; 290: C1067-C1075
        • Kim J.
        • Turan V.
        • Oktay K.
        Long-term safety of letrozole and gonadotrophin stimulation for fertility preservation in women with breast cancer.
        J. Clin. Endocrinol. Metab. 2016; 101: 1364-1371
        • Marjoribanks J.
        • Farquhar C.
        • Roberts H.
        • Lethaby A.
        • Lee J.
        Long-term hormone therapy for perimenopausal and postmenopausal women.
        Cochrane Database Syst. Rev. 2017; 1CD004143
        • Martos M.C.
        • Saurina C.
        • Feja C.
        • Saez M.
        • Burriel M.C.
        • Barceló M.A.
        • Gómez P.
        • Renart G.
        • Alcalá T.
        • Marcos-Gragera R.
        Accurately estimating breast cancer survival in Spain: cross-matching local cancer registries with the National Death Index.
        Rev. Panam. Salud. Pública. 2009; 26: 51-54
        • Mawson A.
        • Lai A.
        • Carroll J.S.
        • Sergio C.M.
        • Mitchell C.J.
        • Sarcevic B.
        oestrogen and insulin/IGF-1 co-operatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1.
        Mol. Cell. Endocrinol. 2005; 229: 161-173
        • Moossdorff M.
        • van Roozendaal L.M.
        • Strobbe L.J.
        • Aebi S.
        • Cameron D.A.
        • Dixon J.M.
        • Giuliano A.E.
        • Haffty B.G.
        • Hickey B.E.
        • Hudis C.A.
        Maastricht Delphi consensus on event definitions for classification of recurrence in breast cancer research.
        J. Natl. Cancer Inst. 2014; 7: 106
        • Moschetti I.
        • Cinquini M.
        • Lambertini M.
        • Levaggi A.
        • Liberati A.
        Follow-up strategies for women treated for early breast cancer.
        Cochrane Database Syst. Rev. 2016; CD001768
        • Oktay K.
        • Buyuk E.
        • Libertella N.
        • Akar M.
        • Rosenwaks Z.
        Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation.
        J. Clin. Oncol. 2005; 23: 4347-4353
        • Oktay K.
        • Hourvitz A.
        • Sahin G.
        • Oktem O.
        • Safro B.
        • Cil A.
        • Bang H.
        Letrozole reduces oestrogen and gonadotrophin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy.
        J. Clin. Endocrinol. Metab. 2006; 91: 3885-3890
        • Oktay K.
        Further evidence on the safety and success of ovarian stimulation with letrozole and tamoxifen in breast cancer patients undergoing in vitro fertilization to cryopreserve their embryos for fertility preservation.
        J. Clin. Oncol. 2005; 23: 3858-3859
        • Orgeas C.C.
        • Sanner K.
        • Hall P.
        • Conner P.
        • Holte J.
        • Nilsson S.J.
        • Sundfeldt K.
        • Persson I.
        • Chia K.S.
        Breast cancer incidence after hormonal infertility treatment in Sweden: a cohort study.
        Am. J. Obstet. Gynecol. 2009; 72 (200): e1-e7
        • Reddy J.
        • Oktay K.
        Ovarian stimulation and fertility preservation with the use of aromatase inhibitors in women with breast cancer.
        Fertil. Steril. 2012; 98: 1363-1369
        • Reigstad M.M.
        • Larsen I.K.
        • Myklebust T.Å.
        • Robsahm T.E.
        • Oldereid N.B.
        • Omland A.K.
        • Vangen S.
        • Brinton L.A.
        • Storeng R.
        Cancer risk among parous women following assisted reproductive technology.
        Hum. Reprod. 2015; 30: 1952-1963
        • Rizzuto I.
        • Behrens R.F.
        • Smith L.A.
        Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility.
        Cochrane Database Syst. Rev. 2013; 13CD008215
        • Siristatidis C.
        • Sergentanis T.N.
        • Kanavidis P.
        • Trivella M.
        • Sotiraki M.
        • Mavromatis I.
        • Psaltopoulou T.
        • Skalkidou A.
        • Petridou E.T.
        Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer- a systematic review and meta-analysis.
        Human Reprod. Update. 2013; 19: 105-123
        • Stewart L.M.
        • Holman C.D.
        • Hart R.
        • Bulsara M.K.
        • Preen D.B.
        • Finn J.C.
        In vitro fertilization and breast cancer: is there cause for concern?.
        Fertil. Steril. 2012; 98: 334-340
        • Valachis A.
        • Mamounas E.P.
        • Mittendorf E.A.
        • Hayashi N.
        • Ishitobi M.
        • Natoli C.
        • Fitzal F.
        • Rubio I.T.
        • Tiezzi D.G.
        • Shin H.C.
        Risk factors for locoregional disease recurrence after breast- conserving therapy in patients with breast cancer treated with neoadjuvant chemotherapy: An international collaboration and individual patient meta-analysis.
        Cancer. 2018; 124: 2923-2930
        • Van Leeuwen F.E.
        • Klip H.
        • Mooij T.M.
        • van de Swaluw A.M.
        • Lambalk C.B.
        • Kortman M.
        • Laven J.S.
        • Jansen C.A.
        • Helmerhorst F.M.
        • Cohlen B.J.
        Risk of borderline and invasive ovarian tumours after ovarian stimulation forin vitro fertilization in a large Dutch cohort.
        Hum. Reprod. 2011; 26: 3456-3465
        • Yue W.
        • Yager J.D.
        • Wang J.P.
        • Jupe E.R.
        • Santen R.J.
        oestrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis.
        Steroids. 2013; 78: 161-170


      Elkin Muñoz, Director of IVIRMA Vigo and IVIRMA Coruña, graduated in gynaecology from Cauca University, Colombia, with a PhD in reproductive medicine from Valencia University, Spain. He is a reproductive medicine specialist, Assistant Professor at Vigo University and Associate Editor of international journals, having himself published over 15 peer-reviewed articles.
      Key message
      Ovarian stimulation for fertility preservation in patients with early breast cancer does not affect disease-free survival and overall survival rates.