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Controversies in oncology: which adjuvant endocrine therapy is to be given to premenopausal patients with hormone receptor-positive breast cancer?

2018; Elsevier BV; Volume: 3; Issue: 3 Linguagem: Inglês

10.1136/esmoopen-2018-000350

ISSN

2059-7029

Autores

Matteo Lambertini, Giulia Viglietti, Evandro de Azambuja,

Tópico(s)

Estrogen and related hormone effects

Resumo

Although young women with newly diagnosed breast cancer are at increased risk of developing more aggressive tumour subtypes as compared with older patients, most of them are diagnosed with hormone receptor-positive (ie, luminal-like) disease.1.Lambertini M. Pinto A.C. Ameye L. et al.The prognostic performance of adjuvant! Online and Nottingham prognostic index in young breast cancer patients.Br J Cancer. 2016; 115: 1471-1478doi:10.1038/bjc.2016.359Crossref PubMed Scopus (27) Google Scholar Hence, the majority of premenopausal women with early stage breast cancer are candidates to receive adjuvant endocrine therapy. Young age is considered a risk factor for breast cancer recurrence and death, particularly in women with luminal-like breast cancer.2.Partridge A.H. Hughes M.E. Warner E.T. et al.Subtype-dependent relationship between young age at diagnosis and breast cancer survival.J Clin Oncol. 2016; 34: 3308-3314doi:10.1200/JCO.2015.65.8013Crossref PubMed Scopus (225) Google Scholar Hence, the choice of the most appropriate adjuvant endocrine therapy is of crucial importance particularly in premenopausal patients. For more than two decades, tamoxifen alone has been considered the standard of care as adjuvant endocrine therapy for all premenopausal patients with hormone receptor-positive breast cancer.3.Senkus E. Kyriakides S. Penault-Llorca F. et al.Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi7-vi23doi:10.1093/annonc/mdt284Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 4.Burstein H.J. Temin S. Anderson H. et al.Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update.J Clin Oncol. 2014; 32: 2255-2269doi:10.1200/JCO.2013.54.2258Crossref PubMed Scopus (563) Google Scholar Nevertheless, in the last few years, the adjuvant endocrine treatment landscape of premenopausal patients with breast cancer has dramatically changed and the choice of the best approach to be used in this setting has become particularly complex. In fact, important new data on the role of ovarian function suppression (OFS) in addition to tamoxifen or its possible combination with an aromatase inhibitor (AI) have recently become available and should now be discussed with all premenopausal women candidates to receive adjuvant endocrine therapy.5.Lambertini M. Poggio F. Vaglica M. et al.News on the medical treatment of young women with early-stage HER2-negative breast cancer.Expert Opin Pharmacother. 2016; 17: 1643-1655doi:10.1080/14656566.2016.1199685Crossref PubMed Scopus (8) Google Scholar Two studies (the E-3193, INT-01426.Tevaarwerk A.J. Wang M. Zhao F. et al.Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group.J Clin Oncol. 2014; 32: 3948-3958doi:10.1200/JCO.2014.55.6993Crossref PubMed Scopus (91) Google Scholar trials and the Suppression of Ovarian Function Trial (SOFT)7.Francis P.A. Regan M.M. Fleming G.F. et al.Adjuvant ovarian suppression in premenopausal breast cancer.N Engl J Med. 2015; 372: 436-446doi:10.1056/NEJMoa1412379Crossref PubMed Scopus (455) Google Scholar, 8.Fleming G. Francis P.A. Láng I. et al.Abstract GS4-03: randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Update of the SOFT trial.Cancer Res. 2018; 78GS4-03doi:10.1158/1538-7445.SABCS17-GS4-03Google Scholar) provided evidence on the role of OFS in addition to tamoxifen in these patients. In the E-3193, INT-0142 trial, 345 premenopausal women at low clinical risk of recurrence (use of chemotherapy was not allowed) were randomised to receive tamoxifen alone or tamoxifen plus OFS for 5 years.6.Tevaarwerk A.J. Wang M. Zhao F. et al.Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group.J Clin Oncol. 2014; 32: 3948-3958doi:10.1200/JCO.2014.55.6993Crossref PubMed Scopus (91) Google Scholar The SOFT randomly assigned 3066 premenopausal women to receive 5 years of tamoxifen alone, tamoxifen plus OFS or the AI exemestane plus OFS.7.Francis P.A. Regan M.M. Fleming G.F. et al.Adjuvant ovarian suppression in premenopausal breast cancer.N Engl J Med. 2015; 372: 436-446doi:10.1056/NEJMoa1412379Crossref PubMed Scopus (455) Google Scholar, 8.Fleming G. Francis P.A. Láng I. et al.Abstract GS4-03: randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Update of the SOFT trial.Cancer Res. 2018; 78GS4-03doi:10.1158/1538-7445.SABCS17-GS4-03Google Scholar In the primary analysis of the SOFT testing the benefit of adding OFS to tamoxifen, 2033 patients were included of whom 53% received chemotherapy before randomisation due to higher clinical risk of recurrence (importantly, patients with prior exposure to cytotoxic therapy could be enrolled within 8 months after chemotherapy completion only if premenopausal status was confirmed). Taken together, the results from these two trials have suggested that the addition of OFS to tamoxifen does not provide any benefit in women at low clinical risk of recurrence for whom tamoxifen alone should be still considered standard of care.9.Burstein H.J. Lacchetti C. Anderson H. et al.Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline update on ovarian suppression.J Clin Oncol. 2016; 34: 1689-1701doi:10.1200/JCO.2015.65.9573Crossref PubMed Scopus (197) Google Scholar, 10.Paluch-Shimon S. Pagani O. Partridge A.H. et al.ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3).Breast. 2017; 35: 203-217doi:10.1016/j.breast.2017.07.017Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 11.Curigliano G. Burstein H.J. P Winer E. et al.De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of early breast cancer 2017.Ann Oncol. 2017; 28: 1700-1712doi:10.1093/annonc/mdx308Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar On the contrary, the addition of OFS to tamoxifen showed to significantly improve the outcomes of women considered at higher clinical risk of recurrence. At a median follow-up of 8 years, the addition of OFS to tamoxifen in patients exposed to chemotherapy in the SOFT was associated with a 5.3% absolute benefit in disease-free survival (DFS; HR 0.76, 95% CI 0.60 to 0.97) and a 4.3% absolute benefit in overall survival (OS; HR 0.59, 95% CI 0.42 to 0.84).8.Fleming G. Francis P.A. Láng I. et al.Abstract GS4-03: randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Update of the SOFT trial.Cancer Res. 2018; 78GS4-03doi:10.1158/1538-7445.SABCS17-GS4-03Google Scholar The benefit of adding OFS was even greater in patients younger than 35 years of age at the time of diagnosis.12.Saha P. Regan M.M. Pagani O. et al.Treatment efficacy, adherence, and quality of life among women younger than 35 years in the international breast cancer study group TEXT and SOFT adjuvant endocrine therapy trials.J Clin Oncol. 2017; 35: 3113-3122doi:10.1200/JCO.2016.72.0946Crossref PubMed Scopus (69) Google Scholar Importantly, when discussing with patients the combination of tamoxifen plus OFS, women should be made aware of the worse endocrine symptoms and sexual functioning (ie, hot flushes, loss of sexual interest, vaginal dryness and sleep disturbance) experienced with this combination particularly during the first 2 years of therapy and in those with no prior exposure to chemotherapy.13.Ribi K. Luo W. Bernhard J. et al.Adjuvant tamoxifen plus ovarian function suppression versus tamoxifen alone in premenopausal women with early breast cancer: patient-reported outcomes in the suppression of ovarian function trial.J Clin Oncol. 2016; 34: 1601-1610doi:10.1200/JCO.2015.64.8675Crossref PubMed Scopus (77) Google Scholar While the role of OFS in premenopausal patients with higher clinical risk of recurrence (ie, those who are normally candidates also to (neo)adjuvant chemotherapy) is now well established and recommended by all major guidelines,9.Burstein H.J. Lacchetti C. Anderson H. et al.Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline update on ovarian suppression.J Clin Oncol. 2016; 34: 1689-1701doi:10.1200/JCO.2015.65.9573Crossref PubMed Scopus (197) Google Scholar, 10.Paluch-Shimon S. Pagani O. Partridge A.H. et al.ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3).Breast. 2017; 35: 203-217doi:10.1016/j.breast.2017.07.017Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 11.Curigliano G. Burstein H.J. P Winer E. et al.De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of early breast cancer 2017.Ann Oncol. 2017; 28: 1700-1712doi:10.1093/annonc/mdx308Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar the best partner (tamoxifen or an AI) to be combined with OFS remains highly debated. In fact, the combination of an AI plus OFS is now considered another available treatment option for these patients.9.Burstein H.J. Lacchetti C. Anderson H. et al.Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline update on ovarian suppression.J Clin Oncol. 2016; 34: 1689-1701doi:10.1200/JCO.2015.65.9573Crossref PubMed Scopus (197) Google Scholar, 10.Paluch-Shimon S. Pagani O. Partridge A.H. et al.ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3).Breast. 2017; 35: 203-217doi:10.1016/j.breast.2017.07.017Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 11.Curigliano G. Burstein H.J. P Winer E. et al.De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of early breast cancer 2017.Ann Oncol. 2017; 28: 1700-1712doi:10.1093/annonc/mdx308Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar However, the two large studies that investigated this strategy (the Austrian Breast and Colorectal Cancer Study Group 12 (ABCSG-12) trial14.Gnant M. Mlineritsch B. Stoeger H. et al.Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.Ann Oncol. 2015; 26: 313-320doi:10.1093/annonc/mdu544Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar and the joint analysis of the SOFT and Tamoxifen and Exemestane Trial (TEXT)15.Pagani O. Regan M.M. Walley B.A. et al.Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.N Engl J Med. 2014; 371: 107-118doi:10.1056/NEJMoa1404037Crossref PubMed Scopus (442) Google Scholar, 16.Pagani O. Regan M.M. Fleming G.F. et al.Abstract GS4-02: randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials.Cancer Res. 2018; 78GS4-02doi:10.1158/1538-7445.SABCS17-GS4-02Google Scholar) showed conflicting results. In the ABCSG-12 trial, 1803 premenopausal patients at low clinical risk of recurrence (only 5% received neoadjuvant chemotherapy and none received adjuvant cytotoxic therapy) were randomised to receive OFS with goserelin plus tamoxifen or the AI anastrozole with or without zoledronic acid for 3 years.14.Gnant M. Mlineritsch B. Stoeger H. et al.Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.Ann Oncol. 2015; 26: 313-320doi:10.1093/annonc/mdu544Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar With a median follow-up of approximately 8 years, no difference was observed in DFS between the two arms (HR 1.13, 95% CI 0.88 to 1.45), but OS was significantly worse in patients who received anastrozole (HR 1.63, 95% CI 1.05 to 2.52).14.Gnant M. Mlineritsch B. Stoeger H. et al.Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.Ann Oncol. 2015; 26: 313-320doi:10.1093/annonc/mdu544Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar Importantly, it should be noted that differently from the SOFT and TEXT, the ABCSG-12 study included only a patients’ population at low risk of relapse, administering a non-standard 3-year duration of endocrine therapy and adjuvant bisphosphonates in half of the included patients. In the joint analysis of the SOFT and TEXT, 4690 patients were randomised to receive OFS plus tamoxifen or the AI exemestane for 5 years.15.Pagani O. Regan M.M. Walley B.A. et al.Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.N Engl J Med. 2014; 371: 107-118doi:10.1056/NEJMoa1404037Crossref PubMed Scopus (442) Google Scholar, 16.Pagani O. Regan M.M. Fleming G.F. et al.Abstract GS4-02: randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials.Cancer Res. 2018; 78GS4-02doi:10.1158/1538-7445.SABCS17-GS4-02Google Scholar Among these patients, 57% received chemotherapy before randomisation due to higher clinical risk of recurrence (importantly, in the TEXT, OFS with triptorelin was started concomitantly with chemotherapy). Updated results at a median follow-up of 9 years showed that, in the overall study population, OFS plus exemestane significantly improved DFS (4.0% absolute benefit; HR 0.77, 95% CI 0.67 to 0.90) but no difference in OS was observed (HR 0.98, 95% CI 0.79 to 1.22). The benefit was larger in patients who received chemotherapy before adjuvant endocrine therapy.16.Pagani O. Regan M.M. Fleming G.F. et al.Abstract GS4-02: randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials.Cancer Res. 2018; 78GS4-02doi:10.1158/1538-7445.SABCS17-GS4-02Google Scholar To help physicians in individualising endocrine therapy decision-making, a sophisticated analysis using the non-parametric sliding-window subpopulation treatment effect pattern plot (STEPP) methodology was conducted within the SOFT and TEXT.17.Regan M.M. Francis P.A. Pagani O. et al.Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: TEXT and SOFT Trials.J Clin Oncol. 2016; 34: 2221-2231doi:10.1200/JCO.2015.64.3171Crossref PubMed Scopus (125) Google Scholar The authors examined the absolute treatment effect across a continuous composite measure of recurrence risk for each patient determined on the basis of their clinical pathological characteristics (ie, age, nodal status, tumour size, grade, oestrogen and progesterone receptors and Ki67 expression levels). This analysis showed that the greater benefit of combining OFS plus AI was observed in women with high risk of recurrence who received chemotherapy and in those who did not undergo chemotherapy but had higher-risk characteristics. The benefit of OFS plus AI over OFS plus tamoxifen was moderate in patients who received chemotherapy but had an intermediate risk of recurrence.17.Regan M.M. Francis P.A. Pagani O. et al.Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: TEXT and SOFT Trials.J Clin Oncol. 2016; 34: 2221-2231doi:10.1200/JCO.2015.64.3171Crossref PubMed Scopus (125) Google Scholar In the treatment decision-making for the choice between OFS plus tamoxifen or an AI, it is crucial to discuss with all premenopausal patients not only the expected benefit based on the individual risk of recurrence but also the different toxicity profile of these two options, the important issue of compliance and adherence to treatment as well as the timing of administering pharmacological OFS. The patient-reported outcomes of the SOFT and TEXT showed small and similar changes in the global quality of life indicators between the combination of OFS with tamoxifen or exemestane.18.Bernhard J. Luo W. Ribi K. et al.Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials.Lancet Oncol. 2015; 16: 848-858doi:10.1016/S1470-2045(15)00049-2Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar However, these two treatment options showed a different toxicity profile: over the 5 years of treatment, hot flushes and sweats were common with the use of tamoxifen while bone or joint pain, vaginal dryness, greater loss of sexual interest and difficulties of becoming aroused with exemestane.18.Bernhard J. Luo W. Ribi K. et al.Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials.Lancet Oncol. 2015; 16: 848-858doi:10.1016/S1470-2045(15)00049-2Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar Therefore, the different toxicity profile should be clearly discussed individually with all patients before making a final decision considering the major role that these side effects can have on their daily life. Moreover, it should be highlighted that young patients with breast cancer have poor compliance to endocrine therapy19.He W. Fang F. Varnum C. et al.Predictors of discontinuation of adjuvant hormone therapy in patients with breast cancer.J Clin Oncol. 2015; 33: 2262-2269doi:10.1200/JCO.2014.59.3673Crossref PubMed Scopus (64) Google Scholar; fertility concerns are among the key factors for both non-initiation and early discontinuation of such treatment.20.Llarena N.C. Estevez S.L. Tucker S.L. et al.Impact of fertility concerns on tamoxifen initiation and persistence.J Natl Cancer Inst. 2015; 107: djv202doi:10.1093/jnci/djv202Crossref PubMed Scopus (93) Google Scholar, 21.Pagani O. Ruggeri M. Manunta S. et al.Pregnancy after breast cancer: are young patients willing to participate in clinical studies?.Breast. 2015; 24: 201-207doi:10.1016/j.breast.2015.01.005Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar In the SOFT and TEXT, up to 20% of the patients stopped all protocol-assigned therapy earlier than 5 years; the rate of non-adherence to endocrine therapy was even higher for women diagnosed under the age of 35 years with 23% and 25% who interrupted triptorelin and oral endocrine therapy at 4 years, respectively.12.Saha P. Regan M.M. Pagani O. et al.Treatment efficacy, adherence, and quality of life among women younger than 35 years in the international breast cancer study group TEXT and SOFT adjuvant endocrine therapy trials.J Clin Oncol. 2017; 35: 3113-3122doi:10.1200/JCO.2016.72.0946Crossref PubMed Scopus (69) Google Scholar On this regard, it is important to highlight that, for administering AI in premenopausal patients, a complete OFS is required while this is not the case for tamoxifen. This is an issue of crucial importance when pharmacological OFS is used. As shown in the SOFT-EST substudy, the combination of triptorelin and exemestane led to a more profound OFS than triptorelin plus tamoxifen.22.Bellet M. Gray K.P. Francis P.A. et al.Twelve-month estrogen levels in premenopausal women with hormone receptor-positive breast cancer receiving adjuvant triptorelin plus exemestane or tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST Substudy.J Clin Oncol. 2016; 34: 1584-1593doi:10.1200/JCO.2015.61.2259Crossref PubMed Scopus (91) Google Scholar However, up to 20% of the patients undergoing triptorelin plus exemestane had incomplete OFS during treatment; this risk seems to be higher for patients not previously exposed to chemotherapy22.Bellet M. Gray K.P. Francis P.A. et al.Twelve-month estrogen levels in premenopausal women with hormone receptor-positive breast cancer receiving adjuvant triptorelin plus exemestane or tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST Substudy.J Clin Oncol. 2016; 34: 1584-1593doi:10.1200/JCO.2015.61.2259Crossref PubMed Scopus (91) Google Scholar and in those with higher body mass index.22.Bellet M. Gray K.P. Francis P.A. et al.Twelve-month estrogen levels in premenopausal women with hormone receptor-positive breast cancer receiving adjuvant triptorelin plus exemestane or tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST Substudy.J Clin Oncol. 2016; 34: 1584-1593doi:10.1200/JCO.2015.61.2259Crossref PubMed Scopus (91) Google Scholar, 23.Pfeiler G. Königsberg R. Fesl C. et al.Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial.J Clin Oncol. 2011; 29: 2653-2659doi:10.1200/JCO.2010.33.2585Crossref PubMed Scopus (177) Google Scholar Hence, although routine monitoring of estradiol levels in patients undergoing pharmacological OFS is not recommended, when an AI is its partner of choice, physicians should be aware about the possible occurrence of physiological changes suggestive for ovarian function recovery (eg, menstrual resumption and/or cyclical fluctuations in climacteric symptoms).9.Burstein H.J. Lacchetti C. Anderson H. et al.Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline update on ovarian suppression.J Clin Oncol. 2016; 34: 1689-1701doi:10.1200/JCO.2015.65.9573Crossref PubMed Scopus (197) Google Scholar In these cases, the AI should be changed to tamoxifen in addition to OFS. For the same reason, when compliance with monthly injection cannot be guaranteed, the combination of OFS and an AI should not be considered the best treatment approach. Finally, regarding the timing of administering pharmacological OFS in patients who are candidates to chemotherapy, it may be considered to start its use during cytotoxic therapy instead of waiting for the end of treatment. In fact, concurrent administration of OFS and chemotherapy was shown to be safe24.Regan M.M. Walley B.A. Francis P.A. et al.Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT.Ann Oncol. 2017; 28: 2225-2232doi:10.1093/annonc/mdx285Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 25.Lambertini M. Moore H.C.F. Leonard R.C.F. et al.Abstract GS4-01: Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients.Cancer Res. 2018; 78GS4-01doi:10.1158/1538-7445.SABCS17-GS4-01Google Scholar and has the potential to reduce the risk of treatment-induced premature ovarian insufficiency and infertility,26.Moore H.C. Unger J.M. Phillips K.A. et al.Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy.N Engl J Med. 2015; 372: 923-932doi:10.1056/NEJMoa1413204Crossref PubMed Scopus (374) Google Scholar, 27.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: 2632-2640doi:10.1001/jama.2015.17291Crossref PubMed Scopus (152) Google Scholar, 28.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: 1811-1816doi:10.1093/annonc/mdx184Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar an issue of great importance for many young patients with breast cancer. In conclusion, it has become rather complex to decide the best adjuvant endocrine therapy option for a given patient and even more the choice between tamoxifen or an AI when OFS is recommended (figure 1). Importantly, during treatment decision-making, patients should be adequately and extensively informed about the pros and contras of the different options; moreover, they should be closely monitored and engaged during the oncological follow-up to increase their treatment compliance and thus improving their long-term outcomes. Final results of the ongoing phase III HOrmonal adjuvant treatment BOne Effects study (ClinicalTrials.gov Identifier: NCT00412022) are awaited to give further insights on what’s the best choice between tamoxifen and an AI as adjuvant endocrine therapy in premenopausal patients with breast cancer who are candidates to receive OFS. ML acknowledges the support from the European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at Institut Jules Bordet in Brussels (Belgium).

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