How I perform fertility preservation in breast cancer patients

Abstract

Additional age-related issues should be considered when managing breast cancer in young women.1Paluch-Shimon S. Cardoso F. Partridge A.H. et al.ESO-ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4).Ann Oncol. 2020; 31: 674-696Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Among them, the potential consequences of anticancer treatments on ovarian function and fertility potential are of particular concern and need to be addressed as early as possible after diagnosis.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Therefore, current guidelines strongly voice the need to provide proper oncofertility counseling with all patients of reproductive age with newly diagnosed cancer irrespective of its stage.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar This is a crucial step to discuss with all young women their disease and prognosis, the required treatments including their potential gonadotoxicity, the need for contraception during and after active systemic therapies, their future desire of conception, likelihood of pregnancy, its safety and outcomes as well as the available strategies to avoid the negative impact of the proposed treatment on ovarian function and fertility.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Considering the rising trend in delaying childbearing and the suboptimal knowledge of health care providers towards these survivorship issues,4Lambertini M. Di Maio M. Pagani O. et al.The BCY3/BCC 2017 survey on physicians’ knowledge, attitudes and practice towards fertility and pregnancy-related issues in young breast cancer patients.Breast. 2018; 42: 41-49Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar further awareness and education towards optimizing the oncofertility counseling of young women with breast cancer need to be prioritized. To estimate the risk of developing treatment-related premature ovarian insufficiency (POI) and subsequent infertility represents the first important step to achieve during oncofertility counseling.1Paluch-Shimon S. Cardoso F. Partridge A.H. et al.ESO-ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4).Ann Oncol. 2020; 31: 674-696Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Patient-related and disease/treatment-related factors should be considered to provide a proper estimation of gonadotoxicity risk, with age of the patient at diagnosis and type of therapy being the most important factors.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar In young women, there are several issues to be considered when defining POI and infertility. Anticancer therapies can impact female ovarian reserve and reproductive potential beyond possible perturbation in ovarian function.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Several studies are evaluating the clinical utility to assess serum concentrations of anti-Mullerian hormone (AMH) before, during and after treatment, to better estimate the risk of gonadotoxicity.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar A better indicator of treatment effect on women’s ovarian reserve would be crucial for improving this first step of oncofertility counseling. In addition, a better indicator of the gonadotoxic impact of chemotherapy would be of particular relevance in young patients with hormone receptor-positive breast cancer, for whom a proper assessment of their ovarian function after the completion of cytotoxic therapy is needed also to optimize adjuvant endocrine therapy.5Lambertini M. Blondeaux E. Perrone F. Del Mastro L. Improving adjuvant endocrine treatment tailoring in premenopausal women with hormone receptor-positive breast cancer.J Clin Oncol. 2020; 38: 1258-1267Crossref PubMed Scopus (17) Google Scholar Several studies have reported the gonadotoxicity of the most commonly used chemotherapy regimens in premenopausal women with breast cancer using both amenorrhea rates and AMH levels following its administration as the definition of treatment-related POI (Table 1).2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google ScholarTable 1Estimated risk of treatment-related amenorrhea in breast cancer patients receiving systemic anticancer therapiesAdapted from ESMO 2020 guidelines.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google ScholarDegree of riskTreatment type/regimenCommentsHigh risk (>80%)•6 Cycles of CMF, CEF, CAF or TAC in women aged ≥40 yearsSignificant decline in AMH concentrations after treatmentIntermediate risk (20%-80%)•6 Cycles of CMF, CEF, CAF or TAC in women aged 30-39 years•4 Cycles of AC in women aged ≥40 years•4 Cycles of AC/EC → taxane•4 Cycles of dd (F)EC → dd taxaneSignificant decline in AMH concentrations after treatmentLow risk (<20%)•6 Cycles of CMF, CEF, CAF or TAC in women aged <30 years•4 Cycles of AC in women aged <40 yearsSignificant decline in AMH concentrations after treatmentVery low or no risk•Antimetabolites (methotrexate, fluorouracil)•Vinca alkaloids•TamoxifenNo change in AMH concentrations after treatment•Bevacizumab (?)•Trastuzumab, lapatinib and T-DM1 (?)Unknown/unclear risk•Platinum- and taxane-based chemotherapy•Most targeted therapies (including monoclonal antibodies and small molecules): pertuzumab, everolimus, CDK4/6 inhibitors, PARP inhibitors•Immunotherapy•GnRHa plus an aromatase inhibitorWhenever available, data on post-treatment AMH concentrations, that most accurately reflect the potential damage on the ovarian reserve, are reported as commentary.AC, doxorubicin, cyclophosphamide; AMH, anti-Mullerian hormone; CAF, cyclophosphamide, doxorubicin, 5-fluorouracil; CDK4/6, cyclin-dependent kinase 4/6; CEF, cyclophosphamide, epirubicin, 5-fluorouracil; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; dd, dose dense; EC, epirubicin, cyclophosphamide; GnRHa, gonadotropin-releasing hormone agonist; PARP, poly (ADP-ribose) polymerase; TAC, docetaxel, doxorubicin, cyclophosphamide. Open table in a new tab Whenever available, data on post-treatment AMH concentrations, that most accurately reflect the potential damage on the ovarian reserve, are reported as commentary. AC, doxorubicin, cyclophosphamide; AMH, anti-Mullerian hormone; CAF, cyclophosphamide, doxorubicin, 5-fluorouracil; CDK4/6, cyclin-dependent kinase 4/6; CEF, cyclophosphamide, epirubicin, 5-fluorouracil; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; dd, dose dense; EC, epirubicin, cyclophosphamide; GnRHa, gonadotropin-releasing hormone agonist; PARP, poly (ADP-ribose) polymerase; TAC, docetaxel, doxorubicin, cyclophosphamide. The highest gonadotoxic risk in breast cancer is associated with the use of the alkylating agent cyclophosphamide and its dose.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar In premenopausal women with hormone receptor-positive breast cancer, endocrine therapy use for 5-10 years can indirectly affect the ovarian reserve and fertility potential through aging.5Lambertini M. Blondeaux E. Perrone F. Del Mastro L. Improving adjuvant endocrine treatment tailoring in premenopausal women with hormone receptor-positive breast cancer.J Clin Oncol. 2020; 38: 1258-1267Crossref PubMed Scopus (17) Google Scholar In addition, use of tamoxifen following chemotherapy completion can increase the risk of treatment-related amenorrhea, but does not appear to impact the ovarian reserve.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Limited evidence exists on the gonadotoxicity of targeted therapies and no data exist on immune checkpoint inhibitors. A potential negative effect of bevacizumab cannot be excluded, while the anti-human epidermal growth factor receptor 2 agents trastuzumab, lapatinib and T-DM1 appear to be safe for the ovaries.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar However, no strong conclusions can be made in this regard. Collecting prospective information about the functional and endocrinological impact of modern anticancer therapies on women’s gonadal reserve and reproductive outcomes should become a crucial and vital component of drug development.6Anderson R.A. Clatot F. Demeestere I. et al.Cancer survivorship: reproductive health outcomes should be included in standard toxicity assessments.Eur J Cancer. 2021; 144: 310-316Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Age at diagnosis is the most important patient-related factor to be considered when estimating the risk of gonadotoxicity with the proposed treatment.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Pretreatment ovarian reserve measured by AMH concentration (which is strongly related to age) influences the risk of developing treatment-induced POI. Hereditary conditions, and specifically carrying germline pathogenic variants in the BRCA genes, may negatively impact ovarian reserve and performance of fertility preservation strategies, but data are too limited and controversial to conclude about a potential increased risk of treatment-related POI in these patients.7Vuković P. Peccatori F.A. Massarotti C. et al.Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants.Crit Rev Oncol Hematol. 2021; 157: 103201Crossref PubMed Scopus (5) Google Scholar The effect of other factors (including body mass index, smoking history and genetic variants in terms of single-nucleotide polymorphisms) remains to be fully elucidated.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Cryopreservation of oocytes and/or embryos is a standard strategy for fertility preservation and the first option to discuss with all women whenever the ovarian reserve is adequate, a vaginal ultrasound is possible and at least 2 weeks are available before starting anticancer therapy.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar This interval is needed for carrying out ovarian stimulation with gonadotropins before vaginal follicle aspiration followed by cryopreservation (for oocytes) or fertilization and then cryopreservation (for embryos). With ‘random start stimulation’ protocols, ovarian stimulation can also be initiated any time during the menstrual cycle.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar The success of this strategy is strongly dependent on the number of mature oocytes collected after ovarian stimulation, which is directly linked with the age of the patient and her ovarian reserve at diagnosis.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar A live birth rate >40% can be estimated in women younger than 35 years, and <30% in older patients, with a very low success after the age of 40 years.8Cobo A. García-Velasco J. Domingo J. et al.Elective and onco-fertility preservation: factors related to IVF outcomes.Hum Reprod. 2018; 33: 2222-2231Crossref PubMed Scopus (80) Google Scholar Although there is no apparent negative influence of breast cancer diagnosis on the success of the procedure, some evidence suggests a potential reduced performance of oocyte/embryo cryopreservation in breast cancer patients carrying germline BRCA pathogenic variants.7Vuković P. Peccatori F.A. Massarotti C. et al.Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants.Crit Rev Oncol Hematol. 2021; 157: 103201Crossref PubMed Scopus (5) Google Scholar However, oocyte/embryo cryopreservation remains the first option to be discussed also in BRCA-mutated breast cancer patients.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Importantly, this strategy allows access to preimplantation genetic testing that can be of importance for these women.7Vuković P. Peccatori F.A. Massarotti C. et al.Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants.Crit Rev Oncol Hematol. 2021; 157: 103201Crossref PubMed Scopus (5) Google Scholar Safety concerns have been raised with the use of ovarian stimulation for approximately 2 weeks in women newly diagnosed with breast cancer and particularly in those with hormone receptor-positive disease.4Lambertini M. Di Maio M. Pagani O. et al.The BCY3/BCC 2017 survey on physicians’ knowledge, attitudes and practice towards fertility and pregnancy-related issues in young breast cancer patients.Breast. 2018; 42: 41-49Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar However, despite the limited evidence, available data support the safety of carrying out ovarian stimulation after diagnosis and before starting adjuvant or neoadjuvant chemotherapy.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar The addition of letrozole during ovarian stimulation may help to reduce estradiol concentrations without any apparent negative effect on the efficacy of the strategy.9Bonardi B. Massarotti C. Bruzzone M. et al.Efficacy and safety of controlled ovarian stimulation with or without letrozole co-administration for fertility preservation: a systematic review and meta-analysis.Front Oncol. 2020; 10: 574669Crossref PubMed Scopus (6) Google Scholar Therefore, the inclusion of letrozole in the protocols for ovarian stimulation in breast cancer patients may be considered the preferred approach.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Ovarian tissue cryopreservation is an alternative approach to preserve fertility (and ovarian function) when oocyte/embryo cryopreservation is not feasible.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar It consists of ovarian cortex biopsies or unilateral ovariectomy usually carried out by laparoscopy under general anesthesia, followed by cryopreservation. Thawing and subsequent transplantation (most often done orthotopically to allow spontaneous pregnancies) can be carried out any time following anticancer treatment completion if there is no spontaneous resumption of ovarian function or natural conception. Importantly, this strategy does not require ovarian stimulation and anticancer treatments can be started the day after the procedure.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar There are two crucial factors for the success of ovarian tissue cryopreservation: the expertise of the laboratory in cryopreserving the tissue and the age of the patient at the time of the procedure. With a ‘hub and spoke’ model, regional networks should be implemented to optimize the success of this strategy, with the possibility to carry out the surgery locally while referring the tissue to a central experienced facility for cryostorage.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar In terms of age, only a few pregnancies have been obtained in women older than 36 years, thus supporting this age as the cut-off point to propose ovarian tissue cryopreservation.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar With these caveats, a live birth rate of around 40% is expected, with approximately half of the pregnancies being spontaneous.10Gellert S.E. Pors S.E. Kristensen S.G. et al.Transplantation of frozen-thawed ovarian tissue: an update on worldwide activity published in peer-reviewed papers and on the Danish cohort.J Assist Reprod Genet. 2018; 35: 561-570Crossref PubMed Scopus (101) Google Scholar In terms of safety, the risks and complications related to the procedure are low in women without contraindication to surgery/anaesthesia.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar In women with early breast cancer, the risk of disease transmission during transplantation due to residual neoplastic cells within the ovarian cortex is considered low, but it is crucial to use adequate techniques to exclude malignant contamination of the cryopreserved tissue.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Caution is needed in women at increased risk of ovarian cancer due to hereditary predisposition (e.g. because of germline BRCA pathogenic variants). Limited evidence is available in this setting.7Vuković P. Peccatori F.A. Massarotti C. et al.Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants.Crit Rev Oncol Hematol. 2021; 157: 103201Crossref PubMed Scopus (5) Google Scholar However, ovarian tissue cryopreservation carried out years before the recommended age of risk-reducing gynecological surgery is not contraindicated per se, although specific considerations are needed including the choice of the transplantation site.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar In premenopausal breast cancer patients, medical gonadoprotection obtained by administering gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is standard strategy for ovarian function preservation.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar This option aims at reducing POI risk and all its associated endocrine-related side-effects. Therefore, it can be considered highly relevant also to women without pregnancy desire and not interested in fertility preservation strategies. GnRHa use during chemotherapy should not be considered as a stand-alone fertility preservation strategy but can be used in conjunction with cryopreservation options.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar A large meta-analysis based on individual patient-level data from 873 patients randomized in five major breast cancer trials reported the efficacy and safety of this strategy.11Lambertini M. Moore H.C.F. Leonard R.C.F. et al.Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data.J Clin Oncol. 2018; 36: 1981-1990Crossref PubMed Scopus (122) Google Scholar Administering GnRHa during chemotherapy significantly reduces POI rates [from 30.9% to 14.1%; adjusted odds ratio (OR) 0.38; 95% confidence intervals (CI) 0.26-0.57]. Treatment benefit was observed in both patients younger or older than 40 years and in both women with hormone receptor-positive and -negative breast cancer. Despite the low numbers, more post-treatment pregnancies were observed in women treated with GnRHa during chemotherapy compared with those who received cytotoxic therapy alone (37 versus 20 pregnancies; incidence rate ratio 1.83, 95% CI 1.06-3.15).11Lambertini M. Moore H.C.F. Leonard R.C.F. et al.Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data.J Clin Oncol. 2018; 36: 1981-1990Crossref PubMed Scopus (122) Google Scholar Concurrent use of GnRHa during chemotherapy was shown to be safe with similar disease-free survival [adjusted hazard ratio (HR) 1.01; 95% CI 0.72-1.42] and overall survival (adjusted HR 0.67; 95% CI 0.42-1.06) in patients treated with or without pharmacological ovarian suppression during cytotoxic therapy. The safety of this strategy was observed irrespective of hormone receptor status.11Lambertini M. Moore H.C.F. Leonard R.C.F. et al.Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data.J Clin Oncol. 2018; 36: 1981-1990Crossref PubMed Scopus (122) Google Scholar However, in premenopausal women with hormone receptor-positive breast cancer, subsequent ovarian function suppression should be considered as adjuvant endocrine therapy for most of these patients previously exposed to chemotherapy.1Paluch-Shimon S. Cardoso F. Partridge A.H. et al.ESO-ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4).Ann Oncol. 2020; 31: 674-696Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar,5Lambertini M. Blondeaux E. Perrone F. Del Mastro L. Improving adjuvant endocrine treatment tailoring in premenopausal women with hormone receptor-positive breast cancer.J Clin Oncol. 2020; 38: 1258-1267Crossref PubMed Scopus (17) Google Scholar Breast cancer survivors have a significantly reduced likelihood of having a subsequent pregnancy compared with the general population, with an estimated 60% lower prevalence (relative risk 0.40; 95% CI 0.32-0.49).12Blondeaux E, Perachino M, Bruzzone M, et al. Chances of pregnancy after breast cancer, reproductive and disease outcomes: a systematic review and meta-analysis. San Antonio Breast Cancer Symposium 2021; abstract.Google Scholar Possible explanations for these findings are the concerns shared by both patients and their health care providers that a prior exposure to systemic anticancer treatment may negatively affect the pregnancy itself (by increasing the risk of complications) and that conceiving in women with a prior history of breast cancer may potentially have a detrimental prognostic effect (by increasing the risk of recurrence), particularly in the case of hormone receptor-positive disease.4Lambertini M. Di Maio M. Pagani O. et al.The BCY3/BCC 2017 survey on physicians’ knowledge, attitudes and practice towards fertility and pregnancy-related issues in young breast cancer patients.Breast. 2018; 42: 41-49Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar These concerns have been recently dispelled by a large systematic review and meta-analysis.12Blondeaux E, Perachino M, Bruzzone M, et al. Chances of pregnancy after breast cancer, reproductive and disease outcomes: a systematic review and meta-analysis. San Antonio Breast Cancer Symposium 2021; abstract.Google Scholar No alarming signals were observed for the majority of the analyzed reproductive outcomes including no significant increased risk of congenital abnormalities. However, compared with the general population, breast cancer patients showed an increased risk of undergoing caesarean section (OR 1.14; 95% CI 1.04-1.25), to have offspring with low birth weight (OR 1.50; 95% CI 1.31-1.73), preterm birth (OR 1.45; 95% CI 1.11-1.88) and small for gestational age (OR 1.16; 95% CI 1.01-1.33). The risk of developing these complications, which appeared to be mostly restricted to patients previously exposed to chemotherapy, suggests the need for a close monitoring of these pregnancies in experienced units.12Blondeaux E, Perachino M, Bruzzone M, et al. Chances of pregnancy after breast cancer, reproductive and disease outcomes: a systematic review and meta-analysis. San Antonio Breast Cancer Symposium 2021; abstract.Google Scholar In terms of patients’ prognosis, no detrimental effect of pregnancy after breast cancer was shown, even when correcting for the potential guarantee-time bias (including the possible ‘healthy mother effect’). Patients with a post-treatment pregnancy showed a better disease-free survival (HR 0.73; 95% CI 0.56-0.94; HR adjusted for guarantee-time bias 0.74; 95% CI 0.58-0.96) and overall survival (HR 0.56; 95% CI 0.46-0.67; HR adjusted for guarantee-time bias 0.52; 95% CI 0.42-0.65) compared with women with breast cancer without subsequent pregnancy. The safety of pregnancy was observed irrespective of patient, tumor, treatment characteristics, timing and outcome of pregnancy.12Blondeaux E, Perachino M, Bruzzone M, et al. Chances of pregnancy after breast cancer, reproductive and disease outcomes: a systematic review and meta-analysis. San Antonio Breast Cancer Symposium 2021; abstract.Google Scholar Based on the reassuring growing body of knowledge on the topic, pregnancy in women with a prior history of breast cancer should not be discouraged following proper treatment and follow-up.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar The prospective POSITIVE trial (NCT02308085) has recently completed accrual and will report on the safety of a temporary interruption of adjuvant endocrine therapy to attempt pregnancy in women with hormone receptor-positive breast cancer.13Sun Z. Niman S.M. Pagani O. et al.Estimation of historical control rate for a single arm de-escalation study – Application to the POSITIVE trial.Breast. 2020; 53: 1-7Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Nowadays, giving hope for a family after cancer diagnosis and treatment should be considered a crucial ambition in cancer care.14Perachino M. Massarotti C. Razeti M.G. et al.Gender-specific aspects related to type of fertility preservation strategies and access to fertility care.ESMO Open. 2020; 5: e000771PubMed Scopus (2) Google Scholar Therefore, oncofertility care has become a priority and a mandatory component of the management of young women with newly diagnosed breast cancer.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar Increased awareness by all health care professionals in oncology is needed to make sure this topic is always discussed at diagnosis and women can make fully informed decisions about the proposed anticancer therapies and their potential interest in accessing the available strategies for ovarian function and/or fertility preservation.2Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,3Anderson R.A. Amant F. Braat D. et al.ESHRE Guideline Group on female fertility preservationESHRE guideline: female fertility preservation.Hum Reprod Open. 2020; : hoaa052Crossref PubMed Google Scholar