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Gonadotropin-releasing hormone analogs for ovarian function protection during chemotherapy in young early breast cancer patients: the last piece of the puzzle?

2017; Elsevier BV; Volume: 28; Issue: 8 Linguagem: Inglês

10.1093/annonc/mdx277

1569-8041

Lucia Del Mastro, Matteo Lambertini,

Ovarian cancer diagnosis and treatment

In western countries, nearly 6% of women with newly diagnosed breast cancer are younger than 40 years old [1.Brinton L.A. Sherman M.E. Carreon J.D. Anderson WF. Recent trends in breast cancer among younger women in the United States.J Natl Cancer Inst. 2008; 100: 1643-1648Crossref PubMed Scopus (204) Google Scholar]. This percentage rises to 25% in developing countries [2.Elkum N. Dermime S. Ajarim D. et al.Being 40 or younger is an independent risk factor for relapse in operable breast cancer patients: the Saudi Arabia experience.BMC Cancer. 2007; 7: 222.Crossref PubMed Scopus (79) Google Scholar]. At least half of young women with breast cancer desire children after treatment [3.Letourneau J.M. Smith J.F. Ebbel E.E. et al.Racial, socioeconomic, and demographic disparities in access to fertility preservation in young women diagnosed with cancer.Cancer. 2012; 118: 4579-4588Crossref PubMed Scopus (128) Google Scholar]. Nevertheless, breast cancer patients have the lowest chances among cancer survivors to subsequently become pregnant [4.Peccatori F.A. Azim Jr, H.A. Orecchia R. et al.Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi160-vi170Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar]. A potential important cause of such a low pregnancy rate in breast cancer survivors is represented by the possible gonadal damage induced by anticancer systemic therapies [5.Lambertini M. Del Mastro L. Pescio M.C. et al.Cancer and fertility preservation: international recommendations from an expert meeting.BMC Med. 2016; 14: 1.Crossref PubMed Scopus (265) Google Scholar]. At the time of treatment decision-making, ∼50% of young breast cancer patients are concerned about the potential risk of developing chemotherapy-induced premature ovarian failure (POF) and subsequent fertility impairment [6.Ruddy K.J. Gelber S.I. Tamimi R.M. et al.Prospective study of fertility concerns and preservation strategies in young women with breast cancer.J Clin Oncol. 2014; 32: 1151-1156Crossref PubMed Scopus (245) Google Scholar]. Embryo or oocyte cryopreservation is considered standard fertility preserving techniques but they cannot protect gonadal function during chemotherapy [4.Peccatori F.A. Azim Jr, H.A. Orecchia R. et al.Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi160-vi170Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar, 7.Loren A.W. Mangu P.B. Beck L.N. et al.Fertility preservation for patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update.J Clin Oncol. 2013; 31: 2500-2510Crossref PubMed Scopus (1130) Google Scholar]. Temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy is another available option that has been mainly investigated as a strategy to preserve ovarian function during systemic cytotoxic therapy [5.Lambertini M. Del Mastro L. Pescio M.C. et al.Cancer and fertility preservation: international recommendations from an expert meeting.BMC Med. 2016; 14: 1.Crossref PubMed Scopus (265) Google Scholar]. However, this strategy has been widely debated in the last years with supporters [8.Blumenfeld Z. Pregnancy rate and preservation of cyclic ovarian function with gonadotropin-releasing hormone agonist cotreatment during chemotherapy.JAMA Oncol. 2016; 2: 545-546Crossref PubMed Scopus (2) Google Scholar] and strong detractors [9.Oktay K. Turan V. Failure of ovarian suppression with gonadotropin-releasing hormone analogs to preserve fertility: an assessment based on the quality of evidence.JAMA Oncol. 2016; 2: 74-75Crossref PubMed Scopus (23) Google Scholar] of its protective role. The OPTION study, published in this issue of Annals of Oncology, provides additional insights on the efficacy of GnRHa as a strategy to preserve ovarian function during chemotherapy [10.Leonard R.C.F. Adamson D.J.A. Bertelli G. et al.GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial.Ann Oncol. 2017; 28: 1811-1816Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. In this phase III study, 227 premenopausal breast cancer patients were randomized to receive adjuvant or neo-adjuvant chemotherapy alone (control group) or with concurrent administration of the GnRHa goserelin for the whole duration of systemic cytotoxic therapy (experimental group). Primary analysis was carried out in 202 patients (89% of the population randomized in the study). The study showed that concurrent use of GnRHa during chemotherapy was associated with a reduced incidence of amenorrhea (defined as no menses between 12 and 24 months after randomization), from 38.3% in the control group to 22.1% in the experimental group (P = 0.015). The protective effect of the GnRHa goserelin was also confirmed by the secondary analysis in which a composite endpoint was used to define chemotherapy-induced POF, i.e. amenorrhea and follicle-stimulating hormone values above 25 IU/l. This analysis was conducted in 131 patients (58% of the population randomized in the study): the incidence of chemotherapy-induced POF was 34.8% in the control group when compared with 18.5% in the experimental group (P = 0.048). The protective effect was more prominent in patients aged ≤40 years: in this subgroup of women, the incidence of amenorrhea decreased from 25.4% to 10.0% (P = 0.032) and the incidence of chemotherapy-induced POF from 20.0% to 2.6% (P = 0.038) when GnRHa was added to chemotherapy. On the contrary, in patients older than 40 years the difference in the incidence of both amenorrhea and chemotherapy-induced POF between the control and experimental groups was not statistically significant. Although no standard definition of chemotherapy-induced POF exists so far, it has been recently proposed that anti-Mullerian hormone (AMH), a reliable hallmark of ovarian reserve, may become a biomarker of gonadotoxicity following the use of anticancer systemic therapies [11.Bozza C. Puglisi F. Lambertini M. et al.Anti-Mullerian hormone: determination of ovarian reserve in early breast cancer patients.Endocr Relat Cancer. 2014; 21: R51-R65Crossref PubMed Scopus (28) Google Scholar, 12.Dezellus A. Barriere P. Campone M. et al.Prospective evaluation of serum anti-Müllerian hormone dynamics in 250 women of reproductive age treated with chemotherapy for breast cancer.Eur J Cancer. 2017; 79: 72-80Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. Secondary results from the OPTION study showed a marked fall of AMH values after chemotherapy in both treatment arms with no difference between the control and experimental groups. Taking into account these findings, the authors concluded that the amount of ovarian function preserved by the use of GnRHa may be relatively small. However, the limited number of patients with available AMH values (109 women at 24 months, 48% of the population randomized in the study) does limit the reliability of this analysis [10.Leonard R.C.F. Adamson D.J.A. Bertelli G. et al.GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial.Ann Oncol. 2017; 28: 1811-1816Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. The results of the OPTION study showing a beneficial effect of temporary ovarian suppression with GnRHa during chemotherapy in preserving ovarian function are consistent with those of the other largest studies that have recently investigated the efficacy of this strategy in breast cancer patients [13.Del Mastro L. Boni L. Michelotti A. et al.Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.JAMA. 2011; 306: 269-276Crossref PubMed Scopus (308) Google Scholar]. Along the same direction, our updated meta-analysis including 12 randomized controlled trials that assessed the role of temporary ovarian suppression with GnRHa during chemotherapy in 1231 premenopausal breast cancer patients confirmed the protective effective of this strategy [16.Lambertini M. Ceppi M. Poggio F. et al.Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies.Ann Oncol. 2015; 26: 2408-2419Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. We observed that the concurrent use of GnRHa during chemotherapy was associated with more than 60% reduction in the risk of developing chemotherapy-induced POF (odds ratio [OR] 0.36, 95% confidence intervals [CI] 0.23–0.57, P < 0.001) [16.Lambertini M. Ceppi M. Poggio F. et al.Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies.Ann Oncol. 2015; 26: 2408-2419Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. If the results of the largest phase III studies, including those of the OPTION trial as well as the findings of our meta-analysis, consistently show the beneficial effect of temporary ovarian suppression with GnRHa during chemotherapy in ovarian function protection, why is its role still debated? Skepticism about this strategy primarily relies on the fact that the main outcome investigated in all the trials was not represented by long-term pregnancy rate but resumption of menses that may not be a good surrogate of fertility restoration. Nevertheless, including data coming from the recent largest studies [14.Lambertini M. Boni L. Michelotti A. et al.Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival. A randomized clinical trial.JAMA. 2015; 314: 2632-2640Crossref PubMed Scopus (155) Google Scholar, 15.Moore H.C.F. Unger J.M. Phillips K.-A. et al.Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy.N Engl J Med. 2015; 372: 923-932Crossref PubMed Scopus (378) Google Scholar], our meta-analysis showed a higher pregnancy rate in women treated with GnRHa than in those who received chemotherapy alone (OR 1.83, 95% CI 1.02–3.28, P = 0.041) [16.Lambertini M. Ceppi M. Poggio F. et al.Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies.Ann Oncol. 2015; 26: 2408-2419Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. Therefore, although the numbers remain relatively small (33 vs. 19 women with a subsequent pregnancy), these data suggest the possible additional role of temporary ovarian suppression with GnRHa during chemotherapy as a strategy not only for ovarian function protection but also for fertility preservation. Although the difference was not statistically significant, more pregnancies were observed in patients receiving GnRHa when compared with those treated with chemotherapy alone also in the OPTION study (9 vs. 6 pregnancies) [10.Leonard R.C.F. Adamson D.J.A. Bertelli G. et al.GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial.Ann Oncol. 2017; 28: 1811-1816Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. On the basis of the growing amount of evidence on the protective role of temporary ovarian suppression with GnRHa during chemotherapy, several guidelines have been recently updated to acknowledge the possibility of discussing this strategy with young breast cancer patients interested in preserving fertility and/or ovarian function [17.Coates A.S. Winer E.P. Goldhirsch A. et al.Tailoring therapies-improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015.Ann Oncol. 2015; 26: 1533-1546Abstract Full Text Full Text PDF PubMed Scopus (1306) Google Scholar, 18.Paluch-Shimon S. Pagani O. Partridge A.H. et al.Second international consensus guidelines for breast cancer in young women (BCY2).Breast. 2016; 26: 87-99Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 19.Gradishar W.J. Anderson B.O. Balassanian R. et al.NCCN guidelines insights: breast cancer, Version 1.2017.J Natl Compr Canc Netw. 2017; 15: 433-451Crossref PubMed Scopus (286) Google Scholar, 20.Lambertini M. Cinquini M. Moschetti I. et al.Temporary ovarian suppression during chemotherapy to preserve ovarian function and fertility in breast cancer patients: A GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.Eur J Cancer. 2017; 71: 25-33Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. The results of the OPTION study further strengthen this recommendation. Embryo or oocyte cryopreservation remains the first strategies to be proposed in patients willing to preserve fertility before starting anticancer systemic therapies. Temporary ovarian suppression with GnRHa during chemotherapy should now be considered another standard option that is not an alternative nor mutually exclusive with the surgical strategies. With the results of the OPTION study, has the puzzle on the protective role of temporary ovarian suppression with GnRHa during chemotherapy been completed? We believe that the answer should be ‘yes’. Nevertheless, an individual patient-data meta-analysis of randomized controlled trials investigating the role of temporary ovarian suppression with GnRHa during chemotherapy in breast cancer patients is currently ongoing (PROSPERO registration number: CRD42014015638) [5.Lambertini M. Del Mastro L. Pescio M.C. et al.Cancer and fertility preservation: international recommendations from an expert meeting.BMC Med. 2016; 14: 1.Crossref PubMed Scopus (265) Google Scholar]. Final results of this meta-analysis, expected for the end of 2017, are awaited to better identify those patients who are more likely to benefit from the use of this strategy. Matteo Lambertini acknowledges the support from the European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at Institut Jules Bordet. This work was partially supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC; investigator grant no: 2013-14272). The study funder had no role in the interpretation of these data, the writing of the manuscript, nor the decision to submit the editorial for publication.