{"paper_id":"47fb1af2-43be-4275-9961-46ade269cad0","body_text":"Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial MARIA VITTORIA DIECI, GIANCARLO BISAGNI, STEFANIA BARTOLINI, ANTONIO FRASSOLDATI, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2063715/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background We evaluated the impact of the type of endocrine therapy on disease-free survival (DFS) in patients with HR-positive/HER2-positive BC enrolled in the phase III ShortHER trial. Methods Short-HER randomized 1254 patients with HER2-positive early BC to 9 weeks vs 1 year of adjuvant trastuzumab combined with anthracycline-taxane chemotherapy. The type of adjuvant endocrine was collected during the first 5 years of follow-up and was classified as: aromatase inhibitor (AI), tamoxifen and aromatase inhibitor (TAM-AI), or tamoxifen (TAM). The use of gonadotropin-releasing hormone analogues (GnRHa) was also collected. DFS was calculated from randomization to disease recurrence, second primary tumor, or death. Results 784 patients with HR-positive BC were included: 60.5% postmenopausal, median age 55 years. The pattern of endocrine therapy was: 59.6% AI, 23.8% TAM, 16.6% TAM-AI. At a median follow up of 8.7 years, patients who received AI had a significantly better DFS vs patients who received TAM or TAM-AI: 8-yr DFS 86.4% vs 79.7%, log-rank P = 0.013 (HR 1.52, 95%CI 1.09–2.11). In multivariate analysis, the type of endocrine therapy maintained a significant association with DFS (HR 1.64, 95% CI 1.07–2.52, p = 0.025 for TAM/TAM-AI vs AI). Among premenopausal patients aged ≤ 45 years (97% receiving TAM or TAM-AI), the use of GnRHa was associated with longer DFS: 8-yr DFS rate 85.2% vs 62.6% (log-rank p = 0.019, HR 0.41, 95% CI 0.19–0.88). Conclusions In this post-hoc analysis of the ShortHER trial adjuvant treatment with AI was independently associated with improved DFS. Subgroup analysis in young premenopausal patients suggests benefit with ovarian suppression. Trial registration: NCI ClinicalTrials.gov number: NCT00629278. Registered 5 March 2008. Retrospectively registered (first patient in December 2007). HER2-positive aromatase inhibitor tamoxifen ovarian function suppression adjuvant Figures Figure 1 Figure 2 Figure 3 Introduction Human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) is a heterogeneous disease. The bidirectional cross-talk between the HER2 and the estrogen receptor pathways shapes biological differences in both molecular features and tumor microenvironment between hormone receptor (HR)-positive/HER2-positive and HR-negative/HER2-positive BC[ 1 – 3 ]. Clinical implications include different outcome and treatment sensitivity[ 4 ]. For example, HR-positive/HER2-positive BC patients show a lower risk of relapse in the first 3–5 years after diagnosis as compared to patients with HR-negative/HER2-positive BC, however the risk of relapse may persist longer at a later follow-up[ 5 , 6 ]. In the neoadjuvant setting, HR-positive/HER2-positive BC patients have a reduced chance of achieving a pathological complete response after neoadjuvant chemotherapy and anti-HER2 agents as compared to the HR-negative/HER2-positive subgroup[ 7 , 8 ]. Nevertheless, HR-positive/HER2-positive BC patients derive a similar degree of relative benefit from trastuzumab added to adjuvant chemotherapy[ 9 , 10 ]. Endocrine therapy (ET) is a mainstay of treatment for HR-positive BC. In HR-positive/HER2-positive BC, the cross-talk between the two pathways may determine resistance to endocrine manipulation[ 11 – 14 ]. Co-targeting the HER2 and the estrogen receptor pathway in HR-positive/HER2-positive BC is an effective strategy in the metastatic setting[ 15 , 16 ] and the administration of adjuvant ET for 5–10 years in addition to chemotherapy and anti-HER2 treatment is standard in the adjuvant setting[ 17 ]. Nevertheless, the optimal adjuvant ET for HR-positive/HER2-positive BC patients is still unclear. The 2015 EBCTCG metanalysis established aromatase inhibitors as the preferred treatment for postmenopausal patients with HR-positive BC based on a significant reduction in the risk of relapse of approximately 30% over tamoxifen[ 18 ]. This effect was maintained unchanged in both HER2-positive and HER2-negative BC subgroups[ 18 ]. However, HER2 status was not available for 70% of patients in this metanalysis and the HER2-positive subgroup was limited in sample size. Conversely, a combined analysis of 12,129 postmenopausal patients from three randomized trials of adjuvant ET with centralized HER2 evaluation demonstrated an interaction between type of adjuvant therapy (upfront tamoxifen or aromatase inhibitor) and HER2 status, with patients with HER2-negative disease deriving a greater benefit from aromatase inhibitor (HR 0.70, 95%CI 0.56–0.87) as compared to HER2-positive patients (HR = 1.13, 95%CI 0.75–1.71)[ 19 ]. In premenopausal patients with HR-positive BC undergoing ovarian function suppression (OFS), aromatase inhibitor is superior to tamoxifen as demonstrated by the TEXT and SOFT trials, with a delta in distant disease-free survival (DFS) at 8 years of 4% (HR 0.77, 95%CI 0.67–0.90)[ 20 ]. However, HER2-negative BC patients derived benefit from aromatase inhibitor (5.4% absolute benefit in DFS at 8 years, HR 0.70), whereas tamoxifen was numerically superior in the small HER2-positive subgroup (n = 695, 3.2% difference in DFS at 8 years, HR 1.18, 95% CI 0.80–1.73)[ 20 ]. An important limitation of all these studies is the small proportion of HR-positive/HER2-positive patients who received anti-HER2 therapy as part of the systemic treatment. Therefore, there is the need to assess the optimal ET option for these patients in the context of standard adjuvant treatment including anti-HER2. Methods Study population and adjuvant ET We included in this analysis patients with HR-positive (ER and/or PgR ≥ 10%) and HER2-positive BC enrolled in the ShortHER trial (NCT00629278) comparing 1-year vs 9-week trastuzumab added to to anthracycline/taxane-based chemotherapy. Enrollment started in December 2007 and ended in October 2013. Study characteristics and results are reported elsewhere[ 21 , 22 ]. Adjuvant ET followed local standards according to guidelines. Options included: Tamoxifen (TAM), aromatase inhibitor (AI), or TAM and AI in sequence for postmenopausal patients; TAM with or without OFS, TAM and AI with or without OFS (switch to AI without OFS if postmenopausal status confirmed), AI with OFS for premenopausal patients and, in selected perimenopausal cases achieving amenorrhea following chemotherapy, AI without OFS with close monitoring of FSH, LH, and estradiol levels [ 23 , 24 ]. The type of prescribed adjuvant ET was collected at each follow-up visit during the first 5 years from randomization and was classified as: aromatase inhibitor (AI), tamoxifen (TAM), tamoxifen and aromatase inhibitor (TAM-AI) in case of both drugs were reported in at least two 6-month follow-up visits. For patients in premenopausal status at study entry, OFS by gonadotropin-relasing hormone analogues (GnRHa) was also collected during follow-up. Statistical analysis DFS was calculated from randomization to disease recurrence (locoregional or metastatic), second primary tumor, or death (any cause). OS was calculated from randomization to death. Statistical analyses were performed using IBM SPSS v.24. Kaplan-Meier method was used to estimate survival curves. The log-rank test was used to compare between groups. Cox proportional regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). The significance level was P < 0.05. All tests were two-sided. Results Patients’ characteristics We identified 853 patients with HR-positive/HER2-positive early BC in the ShortHER trial (68% of all randomized patients). Information on the type of adjuvant ET was available for 784 cases (92%). Patients’ characteristics according to the type of ET are shown in Table 1 . More than half of patients (59.6%) received AI as adjuvant ET, 23.8% received TAM and 16.6% TAM-AI. Patients receiving AI were older (p < 0.001) and more frequently in postmenopausal status (p < 0.001) as compared to patients treated with TAM or TAM-AI. There were no significant differences in the type of adjuvant ET according to disease stage, histologic grade and randomization arm. Table 1 Patients’ characteristics according to type of adjuvant endocrine therapy AI, n tot = 467 TAM, n tot = 187 TAM-AI, n = 130 Tot, n = 784 p value n % n % n % n % Age Yrs, median (Q1; Q3) 60 (55; 65) 43 (39;48) 49 (46;54) 55 (47; 63) < 0.001 Menopausal status Premenopause 62 13,3% 162 86,6% 85 65,4% 309 39,5% Postmenopause 404 86,7% 25 13,4% 45 34,6% 474 60,5% < 0.001 Stage I 193 41,3% 73 39,0% 48 36,9% 314 40,1% 0.771 II 199 42,6% 88 47,1% 61 46,9% 348 44,4% III 75 16,1% 26 13,9% 21 16,2% 122 15,6% Histologic Grade 1–2 172 37,1% 64 35,0% 44 33,8% 280 36,1% 0.738 3 291 62,9% 119 65,0% 86 66,2% 496 63,9% Randomization arm Long 242 51,8% 92 49,2% 59 45,4% 393 50,1% 0.413 Short 225 48,2% 95 50,8% 71 54,6% 391 49,9% Abbreviations: n, number; tot, total; yrs, years; Q1, first quartile; Q3, third quartile; AI, aromatase inhibitor; TAM, tamoxifen Survival according to type of adjuvant ET At a median follow up of 8.7 years (95% CI 8.6–8.8), 141 out of 784 patients had a DFS event (18.0%). DFS was significantly different according to the type of adjuvant ET received. At 8 years the DFS rates were: 86.4% for AI, 81.3% for TAM and 77.7% for TAM-AI (log-rank p = 0.032; Fig. 1 A). Univariate cox-regression analyses with the AI group as reference showed an HR of 1.40 (95% CI 0.95–2.08, p = 0.089) for TAM and an HR of 1.68 (95% CI 1.10–2.55, p = 0.016) for TAM-AI. Since the AI group emerged as the one with the most favorable prognosis and patients treated with TAM or TAM-AI showed similar outcomes, we compared DFS for AI-treated vs TAM or TAM-AI-treated patients. DFS rates at 8 years were 86.4% for AI and 79.7% for TAM/TAM-AI, with an absolute difference of 6.7% (log-rank p = 0.013 Fig. 1 B; HR = 1.52, 95% CI 1.09–2.11, p = 0.014). We conducted multivariate cox regression analyses for DFS including type of ET and other factors (Table 2 ). In model 1 we included those factors that were significantly associated with DFS in univariate analysis: type of ET, stage, histologic grade. In model 2 we added menopausal status to factors included in model 1. We decided to include menopausal status since its potential confounding impact in the assessment of the effect of the type of adjuvant ET. In both models, adjuvant ET with TAM or TAM-AI was independently associated with worse DFS (HR 1.42, 95% CI 1.02–1.99, p = 0.040 in model 1; HR 1.64, 95% CI 1.07–2.52, p = 0.025 in model 2). In terms of OS, there was no difference according to ET received (HR 0.89, 95% CI 0.54–1.49, p = 0.0667 for TAM/TAM-AI vs AI). Table 2 Univariate and multivariate cox-regression models for DFS. Univariate Multivariate model 1 Multivariate model 2 HR (95% CI) p HR (95% CI) p HR (95% CI) p AI TAM or TAM-AI Ref 1.52 (1.09–2.11) 0.014 Ref 1.42 (1.02–1.99) 0.040 Ref 1.64 (1.07–2.52) 0.025 Age (continuous) 1.00 (0.98–1.02) 0.998 Stage I Stage II Stage III Ref 1.52 (1.02–2.26) 2.82 (1.80–4.41) 0.040 < 0.001 Ref 1.46 (0.98–2.18) 2.79 (1.78–4.36) 0.066 < 0.001 Ref 1.45 (0.97–2.17) 2.76 (1.77–4.32) 0.071 < 0.001 Histologic Grade 1–2 Histologic Grade 3 Ref 1.79 (1.22–2.63) 0.003 Ref 1.75 (1.19–2.58) 0.004 Ref 1.77 (1.21–2.61) 0.004 Long arm Short arm Ref 1.08 (0.78–1.50) 0.655 - - - - Postmenopausal status Premenopausal status Ref 1.17 (0.84–1.63) 0.369 - - Ref 0.80 (0.51–1.23) 0.303 Abbreviations: AI, aromatase inhibitor; TAM, tamoxifen; HR, hazard ratio; CI, confidence interval; p, p value; Ref, reference. We explored the annual hazard rates of DFS event in order to assess the benefit of AI over time. We excluded TAM-AI treatment from this analysis since this group included both patients switching from TAM to AI and the inverse sequence. As shown in Fig. 2 , the annual hazard rate of DFS event for patients treated with AI were lower as compared to TAM at almost all timepoints considered, suggesting benefit from AI on both early and late events. However, the duration of ET beyond 5 years was unknown, limiting the interpretation of these results. Premenopausal patients We conducted exploratory analyses in the subgroup of 309 patients in premenopausal status at study entry based on the use of GnRHa as part of adjuvant ET. Table 3 summarizes patients’ characteristics according to GnRHa use. Table 3 Patients’ characteristics according to GnRHa use in the premenopausal subgroup. GnRHa use: NO, n = 136 GnRHa use: YES, n = 173 Total P n % n % n % Age Years, median (Q1; Q3) 49 (46; 51) 43 (39; 46) 46 (41; 49) < 0.001 Stage I 61 44,9% 70 40,5% 131 42,4% II 54 39,7% 78 45,1% 132 42,7% III 21 15,4% 25 14,5% 46 14,9% 0.634 Histologic Grade 1–2 39 28,9% 60 35,5% 99 32,6% 3 96 71,1% 109 64,5% 205 67,4% 0.221 Endocrine therapy AI 55 40,4% 7 4,0% 62 20,1% TAM or TAM-AI 81 59,6% 166 96,0% 247 79,9% < 0.001 Treatment arm Long 69 50,7% 83 48,0% 152 49,2% Short 67 49,3% 90 52,0% 157 50,8% 0.630 Abbreviations: GnRH, gonadotropin-releasing hormone; p, p value; Q1, first quartile; Q3, third quartile; AI, aromatase inhibitor; TAM, tamoxifen More than half of patients (56.0%, n = 173) received GnRHa as part of the adjuvant ET. These patients, as compared to those who did not undergo GnRH treatment, were significantly younger (p < 0.001). Almost all patients (96%) undergoing GnRHa received TAM or TAM-AI vs 59.6% not receiving GnRHa (p < 0.001). This apparently counterintuitive result was driven by 55 patients who received AI without GnRHa. This group likely included perimenopausal patients who achieved an effective OFS following chemotherapy for whom clinicians opted for an AI without GnRHa with close monitoring of FSH, LH and estradiol levels. This hypothesis is supported by the median age of this subgroup of patients (premenopausal at study entry, no GnRHa use, treated with AI): 51 years, Q1:48; Q3: 53. In order to avoid potential confounding factors, we explored the impact of GnRHa on DFS by including only premenopausal patients aged ≤ 45 years (n = 147). In this group, 20% of patients did not receive GnRHa, 97% received TAM or TAM-AI, only 4 patients received AI (combined with GnRHa). As shown in Fig. 3 , GnRHa was associated with improved outcome: DFS rates at 8 years were 85.2% vs 62.6%, log-rank p = 0.019 (HR 0.41, 95% CI 0.19–0.88, p = 0.023). Discussion In this work, we show that adjuvant ET with AI is superior to TAM or TAM-AI in terms of DFS for patients with HR-positive/HER2-positive BC receiving adjuvant anthracycline/taxane-based chemotherapy combined with trastuzumab. These results derive from an exploratory analysis of a randomized trial with 8.7 years of median follow up. Conflicting results exist about a potential detrimental effect of HER2 overexpression on TAM efficacy[ 25 – 27 ] and our data add to the ongoing debate about optimal adjuvant ET for patients with HR-positive/HER2-positive BC. The EBCTCG metanalysis did not demonstrate any interaction between HER2 status and benefit from AI over TAM in postmenopausal patients[ 18 ]. However, a recent trial-level metanalysis addressing this clinical question provided contradictory findings. This study included 5,390 HR-positive/HER2-positive BC patients (of whom 2,410 in premenopausal status) from 6 randomized trials: 5 trials of adjuvant ET (TEAM, ATAC, BIG 1–98, TEXT and SOFT) and 1 trial of adjuvant anti-HER2-therapy (ALTTO)[ 28 ]. The results showed no difference in DFS between adjuvant treatment with AI and TAM[ 28 ]. This metanalysis has several limitations. The number of HR-positive/HER2-positive BC patients in most of these studies was small (in the range of 6 to 12%, excluding ALTTO) and HER2 status was not available for a large proportion of patients. Moreover, trastuzumab adjuvant treatment was administered to a minority of patients in the TEAM, ATAC and BIG 1–98 trials, and only to 60% of HR-positive/HER2-positive BC patients from the TEXT and SOFT trials. In addition, the TEAM, ATAC and BIG 1–98 results apply only to treatment and events occurring in the first 2–3 years of adjuvant ET. Conversely, our analysis is based on a randomized trial dedicated to HER2-positive BC patients, includes a large number of cases with HR-positive/HER2-positive BC (n = 784), all treated with standard adjuvant chemotherapy and trastuzumab. The type of ET was collected for the first 5 years of follow up, median follow-up is long (8.7 years) and survival analysis refers to DFS events occurring throughout the follow up period. The superiority of AI demonstrated in our work is consistent with the results of a post-hoc analysis from the ALTTO trial. This analysis shows similarities with our work, since it included a large subgroup of HR-positive/HER2-positive BC patients (3,603, of whom 1,888 premenopausal) from a clinical trial dedicated to HER2-positive BC patients all treated with adjuvant anti-HER2 therapy[ 6 ]. In multivariate analysis, AI was associated with better DFS as compared to TAM (HR 0.70, 95% CI 0.57–0.97)[ 6 ]. Differently to our findings, also TAM-AI was associated with improved DFS as compared to TAM (HR 0.45, 95% CI 0.33–0.61)[ 6 ]. Differences in the classification of the type of ET might have impacted this discrepant finding. In our study we define TAM-AI treatment when each drug was administered for at least 1 year. No information on the methods applied to categorize TAM-AI treatment is available for the ALTTO analysis. Moreover, a slightly higher proportion of postmenopausal patients is included in our cohort (60.7% vs 52.4% in ALTTO). Another difference is the very limited use of OFS in the ALTTO trial (< 1% of the study population). Cumulative evidence suggests that the benefit from AI over TAM in HR-positive/HER2-positive BC patients may be dependent on menopausal status. Despite we show an association with improved DFS for the use of AI over TAM/TAM-AI that is independent from menopausal status in multivariate analysis, our data should be considered more informative for postmenopausal or perimenopausal patients and less informative for true premenopausal patients. Our population includes a large proportion of postmenopausal patients and, among those defined as premenopausal at study entry, there were probably patients in perimenopausal status who achieved effective OFS following chemotherapy. In addition, only few premenopausal patients aged ≤ 45 years received AI, therefore conclusions about the optimal adjuvant ET for premenopausal patients can not be drawn based on our results. In the TEXT and SOFT trials, for patients undergoing OFS, TAM was numerically superior to AI in the subgroup of HER2-positive BC patients[ 20 ]. The recent EBCTCG metanalysis comparing AI vs TAM in the context of OFS for premenopausal patients also suggested greater benefit from AI vs TAM in HER2-negative disease than in HER2-positive disease (RR 0·65 vs 1·08, p = 0·021)[ 29 ]. However, the HER2-positive subgroup was limited in sample size with a small number of events. Moreover, the difference between HER2-positive and HER2-negative tumors did not reach statistical significance[ 29 ]. A population-based cohort study from the Netherlands Cancer Registry including 1,155 HR-positive/HER2-positive BC patients reported a significant benefit from AI over TAM in perimenopausal patients (age < 45 to ≤ 55 years as a proxy), a numerical benefit in postmenopausal patients (age > 55 years), and a lack of benefit for premenopausal patients (age ≤ 45 years)[ 30 ]. Limitations of this analysis are: the heterogeneous administration of adjuvant trastuzumab, the heterogeneous use of OFS for premenopausal patients, and the lack of a clinical definition of menopausal status. However, these findings further support the hypothesis that hormonal microenvironment changes may affect the efficacy of ET in HR+/HER2 + BC patients. A final keypoint of our work is the exploratory analysis on the role of OFS for premenopausal patientsThe addition of GnRHa to ET (mainly TAM or TAM-AI) for premenopausal patients aged ≤ 45 years was associated with a significantly better DFS. Subgroup analyses of the SOFT trial demonstrated improved outcome for OFS added to TAM in HER2-positive disease[ 20 ]. The Dutch population-based cohort study also described a survival benefit when OFS was added to ET for HR+/HER2 + BC patients[ 30 ]. In this work, we demonstrate for the first time the benefit of OFS in the context of a randomized trial including patients all treated with adjuvant chemotherapy and trastuzumab. The low rate GnRHa use in the ALTTO trial limits the possibility to explore this issue in that study[ 6 ]. It has to be noticed that the duration of GnRHa administration was not systematically collected. At the time the trial was conducted the optimal duration of OFS was unknown and OFS was generally administered for 2–5 years[ 31 ]. Our study has limitations. First, this is an unplanned post-hoc analysis. Second, it was not possible to properly assess therapy duration beyond 5 years and treatment adherence/interruptions. Moreover, perimenopausal patients were not clearly defined and other means of OFS beyond GnRHa were not captured after screening. In conclusion, our findings support the use of AI as adjuvant therapy for HR-positive/HER2-positive BC patients in the context of standard adjuvant treatment including chemotherapy and trastuzumab. In premenopausal patients, the use of OFS prolongs DFS. However, the optimal endocrine oral therapy (either AI or TAM) in this subgroup remains unclear and warrants further evaluation in large cohorts of patients treated with standard adjuvant therapy. List Of Abbreviations BC, breast cancer; AI, aromatase inhibitor; TAM, tamoxifen; ET, endocrine therapy; HR, hormone receptor positive; HER2, human epidermal growth factor receptor 2; DFS, disease-free survival; OS, overall survival, GnRHa, gonadotropin-releasing hormone analogues; OFS, ovarian function suppression. Declarations Ethics approval and consent to participate: The trial was approved by local ethical Committees of all participating centers, and conducted in compliance with the principles of Good Clinical Practice and the Declaration of Helsinki. All patients signed an informed consent form. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Consent for publication: not applicaple Competing interests: MVD reports personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Seagen, Gilead, MSD, AstraZeneca, Daiichi Sankyo outside the submitted work. AF reports personal fees from Roche, Novartis, EliLilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, outside the submitted work. PFC reports personal fees from Novartis, EliLilly, AstraZeneca, Tesaro, Daiichi-Sankyo, Gilead, reveal Genomics, BMS, Roche outside the submitted work. VG reports personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Gilead, MSD, Amgen, Sanofi, Merck Serono, Eisai outside the submitted work. The other authors declare no conflict of interest. Funding: This work was supported by Agenzia Italiana del Farmaco (AIFA, grant FARM62MC97), Italian Association for Cancer Research (AIRC, project MFAG 2014 – 15938; to V. Guarneri), funding from the University of Padova—Department of Surgery, Oncology and Gastroenterology DOR 2019 (to V.G., M.V.D., P.F.C.), DOR 2020 (to V.G., M.V.D.), DOR 2021 (M.V.D., G.G.); Fondazione AIRC under 5 per mille 2019 (ID. 22759 program— group leader V.G.), Ricerca Corrente funding from the Italian Ministry of Health. 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Annals of Oncology. 2019;30:1194–220. Bradley R, Braybrooke J, Gray R, Hills RK, Liu Z, Pan H, et al. Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 2022;23:382–92. Bartlett JMS, Ahmed I, Regan MM, Sestak I, Mallon EA, Dell’Orto P, et al. HER2 status predicts for upfront AI benefit: A TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1–98 and TEAM with centrally determined HER2. Eur J Cancer. 2017;79:129–38. Francis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, Láng I, et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. New England Journal of Medicine. 2018;379:122–37. Guarneri V, Frassoldati A, Bruzzi P, D’Amico R, Belfiglio M, Molino A, et al. Multicentric, Randomized Phase III Trial of Two Different Adjuvant Chemotherapy Regimens plus Three Versus Twelve Months of Trastuzumab in Patients with HER2-Positive Breast Cancer (Short-HER Trial; NCT00629278). Clin Breast Cancer. 2008;8:453–6. Conte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, et al. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. Annals of Oncology. 2018;29:2328–33. Linee Guida Neoplasie della Mammella AIOM 2013. Available at http://media.aiom.it/userfiles/files/doc/LG/2013_LG_AIOM_Mammella_V_101013.pdf . 2013. Ortmann O, Pagani O, Jones A, Maass N, Noss D, Rugo H, et al. Which factors should be taken into account in perimenopausal women with early breast cancer who may become eligible for an aromatase inhibitor? Recommendations of an expert panel. Cancer Treat Rev. 2011;37:97–104. de Placido S, de Laurentiis M, Carlomagno C, Gallo C, Perrone F, Pepe S, et al. Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer. Clin Cancer Res. 2003;9:1039–46. Elledge RM, Green S, Ciocca D, Pugh R, Allred DC, Clark GM, et al. HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study. Clin Cancer Res. 1998;4:7–12. Dowsett M, Allred C, Knox J, Quinn E, Salter J, Wale C, et al. Relationship Between Quantitative Estrogen and Progesterone Receptor Expression and Human Epidermal Growth Factor Receptor 2 (HER-2) Status With Recurrence in the Arimidex, Tamoxifen, Alone or in Combination Trial. Journal of Clinical Oncology. 2008;26:1059–65. Peleg Hasson S, Brezis MR, Shachar E, Shachar SS, Wolf I, Sonnenblick A. Adjuvant endocrine therapy in HER2-positive breast cancer patients: systematic review and meta-analysis. ESMO Open. 2021;6:100088. Bradley R, Braybrooke J, Gray R, Hills RK, Liu Z, Pan H, et al. Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 2022;23:382–92. Dackus GMHE, Jóźwiak K, Sonke GS, van der Wall E, van Diest PJ, Hauptmann M, et al. Optimal adjuvant endocrine treatment of ER+/HER2 + breast cancer patients by age at diagnosis: A population-based cohort study. Eur J Cancer. 2018;90:92–101. Senkus E, Kyriakides S, Penault-Llorca F, Poortmans P, Thompson A, Zackrisson S, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2013;24:vi7–23. Additional Declarations Competing interest reported. MVD reports personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Seagen, Gilead, MSD, AstraZeneca, Daiichi Sankyo outside the submitted work. AF reports personal fees from Roche, Novartis, EliLilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, outside the submitted work. PFC reports personal fees from Novartis, EliLilly, AstraZeneca, Tesaro, Daiichi-Sankyo, Gilead, reveal Genomics, BMS, Roche outside the submitted work. VG reports personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Gilead, MSD, Amgen, Sanofi, Merck Serono, Eisai outside the submitted work. The other authors declare no conflict of interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-2063715\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":137673052,\"identity\":\"3981e608-1642-4667-929a-2e0c8ce48ae6\",\"order_by\":0,\"name\":\"MARIA VITTORIA DIECI\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYJCCAwwMEjAGMw8DA2PjA7DIAcYGfFokeJC0NBtAtTTi1AMEYC1AwAwi2GCWYrVGt/3swwM/2yzq7Nl7Hx74wWAtw89+uK2ad4dFHt8B5vYHWLSYnUk3ONjbBnQYz3GDgz0M6TySPYltt3nPSBRL4nCY2YE0hgM8Z4BaJEAMhsM8BjcYgVraJBI34NJy/hnDwT9QLQf/ALXYA7UU49VyIw2orAKi5TDYFgnGNmb8Wp4xHJapkJDsOXMMyDBI55E4k9gsObcN6JfDjI0zsDosjfnjG4M6fvb2NiCjwtqev/34ww9v2+ry+I63P/iARQsaMEAwEyBxRApIIFXDKBgFo2AUDFsAAK13ZQMdsqQ0AAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"University of Padova\",\"correspondingAuthor\":true,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"MARIA\",\"middleName\":\"VITTORIA\",\"lastName\":\"DIECI\",\"suffix\":\"\"},{\"id\":137673053,\"identity\":\"09e921ea-8d19-457c-a5b7-15d54fda48bd\",\"order_by\":1,\"name\":\"GIANCARLO BISAGNI\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Azienda USL-IRCCS Reggio Emilia\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"GIANCARLO\",\"middleName\":\"\",\"lastName\":\"BISAGNI\",\"suffix\":\"\"},{\"id\":137673054,\"identity\":\"6481068b-2dad-4d40-aaf2-c43114a53fe8\",\"order_by\":2,\"name\":\"STEFANIA BARTOLINI\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto delle Scienze Neurologiche di Bologna\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"STEFANIA\",\"middleName\":\"\",\"lastName\":\"BARTOLINI\",\"suffix\":\"\"},{\"id\":137673055,\"identity\":\"5a6e978d-c813-4797-b4fc-b6bbb114a6ac\",\"order_by\":3,\"name\":\"ANTONIO FRASSOLDATI\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"S. Anna University Hospital Ferrara\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"ANTONIO\",\"middleName\":\"\",\"lastName\":\"FRASSOLDATI\",\"suffix\":\"\"},{\"id\":137673056,\"identity\":\"65ee5fd1-f7b8-4004-a72e-e647dbacaa69\",\"order_by\":4,\"name\":\"ROBERTO VICINI\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Modena\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"ROBERTO\",\"middleName\":\"\",\"lastName\":\"VICINI\",\"suffix\":\"\"},{\"id\":137673057,\"identity\":\"69ceef66-7a4e-481d-a486-e2bf51d82b96\",\"order_by\":5,\"name\":\"SARA BALDUZZI\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Modena\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"SARA\",\"middleName\":\"\",\"lastName\":\"BALDUZZI\",\"suffix\":\"\"},{\"id\":137673058,\"identity\":\"b1fdbf28-018f-4da1-8cc4-deb99b14b442\",\"order_by\":6,\"name\":\"ROBERTO D’AMICO\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Modena\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"ROBERTO\",\"middleName\":\"\",\"lastName\":\"D’AMICO\",\"suffix\":\"\"},{\"id\":137673060,\"identity\":\"79d64d93-093f-410f-907a-8c8651c5dc80\",\"order_by\":7,\"name\":\"PIERFRANCO CONTE\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"veneto oncology network\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"PIERFRANCO\",\"middleName\":\"\",\"lastName\":\"CONTE\",\"suffix\":\"\"},{\"id\":137673062,\"identity\":\"7739cd8e-431d-4d44-96c2-2039f7238254\",\"order_by\":8,\"name\":\"VALENTINA GUARNERI\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Padova\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"VALENTINA\",\"middleName\":\"\",\"lastName\":\"GUARNERI\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2022-09-14 07:44:24\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-2063715/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-2063715/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":26880675,\"identity\":\"f321e7e9-f6f5-47d9-ac51-3958db9c704c\",\"added_by\":\"auto\",\"created_at\":\"2022-09-23 14:27:56\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":343341,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eDFS Kaplan-Meier curves according to type of adjuvant ET. \\u003c/strong\\u003eComparison of AI vs TAM-AI vs TAM in Figure 1A; comparison of AI vs TAM/TAM-AI in Figure 1B.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2063715/v1/2d418746718d4b94c899e4f8.png\"},{\"id\":26880677,\"identity\":\"ba9f2c77-e2d7-4515-876c-0fee365cd9d7\",\"added_by\":\"auto\",\"created_at\":\"2022-09-23 14:27:56\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":253677,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eAnnual hazard rates of DFS event for patients treated with AI or TAM. \\u003c/strong\\u003eThe last timepoint considered is 108 months since the very low number of patients at risk at later years.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2063715/v1/ec422244b0b64f65426e6f64.png\"},{\"id\":26880676,\"identity\":\"67c3c6f5-0d7e-4783-8684-7c6bbd69b4e4\",\"added_by\":\"auto\",\"created_at\":\"2022-09-23 14:27:56\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":187803,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eDFS Kaplan-Meier curves according to GnRHa use in premenopausal patients aged \\u003c/strong\\u003e\\u003cu\\u003e\\u003cstrong\\u003e\\u0026lt;\\u003c/strong\\u003e\\u003c/u\\u003e\\u003cstrong\\u003e45 years.\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2063715/v1/c44784e8f61e813f602253da.png\"},{\"id\":26880755,\"identity\":\"214a4b34-68d0-4821-ad0d-68e9744f3547\",\"added_by\":\"auto\",\"created_at\":\"2022-09-23 14:28:05\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":686565,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2063715/v1/0988490b-a44d-4cec-a894-b89d007d41aa.pdf\"},{\"id\":26880731,\"identity\":\"2aefe1f7-f123-48b8-8cca-bd2127cd7dd5\",\"added_by\":\"auto\",\"created_at\":\"2022-09-23 14:28:01\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":686565,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2063715/v1/9138568d-91b5-46cc-839c-ba58cdeea7ca.pdf\"}],\"financialInterests\":\"Competing interest reported. MVD reports personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Seagen, Gilead, MSD, AstraZeneca, Daiichi Sankyo outside the submitted work. AF reports personal fees from Roche, Novartis, EliLilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, outside the submitted work. PFC reports personal fees from Novartis, EliLilly, AstraZeneca, Tesaro, Daiichi-Sankyo, Gilead, reveal Genomics, BMS, Roche outside the submitted work. VG reports personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Gilead, MSD, Amgen, Sanofi, Merck Serono, Eisai outside the submitted work. The other authors declare no conflict of interest.\",\"formattedTitle\":\"Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eHuman epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) is a heterogeneous disease. The bidirectional cross-talk between the HER2 and the estrogen receptor pathways shapes biological differences in both molecular features and tumor microenvironment between hormone receptor (HR)-positive/HER2-positive and HR-negative/HER2-positive BC[\\u003cspan additionalcitationids=\\\"CR2\\\" citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. Clinical implications include different outcome and treatment sensitivity[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. For example, HR-positive/HER2-positive BC patients show a lower risk of relapse in the first 3\\u0026ndash;5 years after diagnosis as compared to patients with HR-negative/HER2-positive BC, however the risk of relapse may persist longer at a later follow-up[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. In the neoadjuvant setting, HR-positive/HER2-positive BC patients have a reduced chance of achieving a pathological complete response after neoadjuvant chemotherapy and anti-HER2 agents as compared to the HR-negative/HER2-positive subgroup[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. Nevertheless, HR-positive/HER2-positive BC patients derive a similar degree of relative benefit from trastuzumab added to adjuvant chemotherapy[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eEndocrine therapy (ET) is a mainstay of treatment for HR-positive BC. In HR-positive/HER2-positive BC, the cross-talk between the two pathways may determine resistance to endocrine manipulation[\\u003cspan additionalcitationids=\\\"CR12 CR13\\\" citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Co-targeting the HER2 and the estrogen receptor pathway in HR-positive/HER2-positive BC is an effective strategy in the metastatic setting[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e] and the administration of adjuvant ET for 5\\u0026ndash;10 years in addition to chemotherapy and anti-HER2 treatment is standard in the adjuvant setting[\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eNevertheless, the optimal adjuvant ET for HR-positive/HER2-positive BC patients is still unclear. The 2015 EBCTCG metanalysis established aromatase inhibitors as the preferred treatment for postmenopausal patients with HR-positive BC based on a significant reduction in the risk of relapse of approximately 30% over tamoxifen[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. This effect was maintained unchanged in both HER2-positive and HER2-negative BC subgroups[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. However, HER2 status was not available for 70% of patients in this metanalysis and the HER2-positive subgroup was limited in sample size. Conversely, a combined analysis of 12,129 postmenopausal patients from three randomized trials of adjuvant ET with centralized HER2 evaluation demonstrated an interaction between type of adjuvant therapy (upfront tamoxifen or aromatase inhibitor) and HER2 status, with patients with HER2-negative disease deriving a greater benefit from aromatase inhibitor (HR 0.70, 95%CI 0.56\\u0026ndash;0.87) as compared to HER2-positive patients (HR\\u0026thinsp;=\\u0026thinsp;1.13, 95%CI 0.75\\u0026ndash;1.71)[\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]. In premenopausal patients with HR-positive BC undergoing ovarian function suppression (OFS), aromatase inhibitor is superior to tamoxifen as demonstrated by the TEXT and SOFT trials, with a delta in distant disease-free survival (DFS) at 8 years of 4% (HR 0.77, 95%CI 0.67\\u0026ndash;0.90)[\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. However, HER2-negative BC patients derived benefit from aromatase inhibitor (5.4% absolute benefit in DFS at 8 years, HR 0.70), whereas tamoxifen was numerically superior in the small HER2-positive subgroup (n\\u0026thinsp;=\\u0026thinsp;695, 3.2% difference in DFS at 8 years, HR 1.18, 95% CI 0.80\\u0026ndash;1.73)[\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eAn important limitation of all these studies is the small proportion of HR-positive/HER2-positive patients who received anti-HER2 therapy as part of the systemic treatment. Therefore, there is the need to assess the optimal ET option for these patients in the context of standard adjuvant treatment including anti-HER2.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv class=\\\"Section2\\\" id=\\\"Sec3\\\"\\u003e\\n \\u003ch2\\u003eStudy population and adjuvant ET\\u003c/h2\\u003e\\n \\u003cp\\u003eWe included in this analysis patients with HR-positive (ER and/or PgR\\u0026thinsp;\\u003cspan class=\\\"Underline\\\" name=\\\"Emphasis\\\" type=\\\"Underline\\\"\\u003e\\u0026ge;\\u003c/span\\u003e\\u0026thinsp;10%) and HER2-positive BC enrolled in the ShortHER trial (NCT00629278) comparing 1-year vs 9-week trastuzumab added to to anthracycline/taxane-based chemotherapy. Enrollment started in December 2007 and ended in October 2013. Study characteristics and results are reported elsewhere[\\u003cspan class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. Adjuvant ET followed local standards according to guidelines. Options included:\\u003c/p\\u003e\\n \\u003cul\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003eTamoxifen (TAM), aromatase inhibitor (AI), or TAM and AI in sequence for postmenopausal patients;\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003eTAM with or without OFS, TAM and AI with or without OFS (switch to AI without OFS if postmenopausal status confirmed), AI with OFS for premenopausal patients and, in selected perimenopausal cases achieving amenorrhea following chemotherapy, AI without OFS with close monitoring of FSH, LH, and estradiol levels [\\u003cspan class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e].\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n \\u003c/ul\\u003e\\n \\u003cp\\u003eThe type of prescribed adjuvant ET was collected at each follow-up visit during the first 5 years from randomization and was classified as:\\u003c/p\\u003e\\n \\u003cul\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003earomatase inhibitor (AI),\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003etamoxifen (TAM),\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n \\u003cli\\u003e\\n \\u003cp\\u003etamoxifen and aromatase inhibitor (TAM-AI) in case of both drugs were reported in at least two 6-month follow-up visits.\\u003c/p\\u003e\\n \\u003c/li\\u003e\\n \\u003c/ul\\u003e\\n \\u003cp\\u003eFor patients in premenopausal status at study entry, OFS by gonadotropin-relasing hormone analogues (GnRHa) was also collected during follow-up.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv class=\\\"Section2\\\" id=\\\"Sec4\\\"\\u003e\\n \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e\\n \\u003cp\\u003eDFS was calculated from randomization to disease recurrence (locoregional or metastatic), second primary tumor, or death (any cause). OS was calculated from randomization to death.\\u003c/p\\u003e\\n \\u003cp\\u003eStatistical analyses were performed using IBM SPSS v.24. Kaplan-Meier method was used to estimate survival curves. The log-rank test was used to compare between groups. Cox proportional regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). The significance level was \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05. All tests were two-sided.\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePatients\\u0026rsquo; characteristics\\u003c/h2\\u003e \\u003cp\\u003eWe identified 853 patients with HR-positive/HER2-positive early BC in the ShortHER trial (68% of all randomized patients). Information on the type of adjuvant ET was available for 784 cases (92%). Patients\\u0026rsquo; characteristics according to the type of ET are shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. More than half of patients (59.6%) received AI as adjuvant ET, 23.8% received TAM and 16.6% TAM-AI. Patients receiving AI were older (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) and more frequently in postmenopausal status (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) as compared to patients treated with TAM or TAM-AI. There were no significant differences in the type of adjuvant ET according to disease stage, histologic grade and randomization arm.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003ePatients\\u0026rsquo; characteristics according to type of adjuvant endocrine therapy\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"11\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c10\\\" colnum=\\\"10\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c11\\\" colnum=\\\"11\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c4\\\" namest=\\\"c3\\\"\\u003e \\u003cp\\u003eAI, n tot\\u0026thinsp;=\\u0026thinsp;467\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e \\u003cp\\u003eTAM, n tot\\u0026thinsp;=\\u0026thinsp;187\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003eTAM-AI, n\\u0026thinsp;=\\u0026thinsp;130\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c10\\\" namest=\\\"c9\\\"\\u003e \\u003cp\\u003eTot, n\\u0026thinsp;=\\u0026thinsp;784\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c11\\\"\\u003e \\u003cp\\u003ep value\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003en\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e%\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003en\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e%\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003en\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e%\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003en\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e%\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eYrs, median (Q1; Q3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c4\\\" namest=\\\"c3\\\"\\u003e \\u003cp\\u003e60 (55; 65)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c6\\\" namest=\\\"c5\\\"\\u003e \\u003cp\\u003e43 (39;48)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003e49 (46;54)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c10\\\" namest=\\\"c9\\\"\\u003e \\u003cp\\u003e55 (47; 63)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eMenopausal status\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePremenopause\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e62\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13,3%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e162\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e86,6%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e85\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e65,4%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e309\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e39,5%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePostmenopause\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e404\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e86,7%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e13,4%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e45\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e34,6%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e474\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e60,5%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"2\\\" rowspan=\\\"3\\\"\\u003e \\u003cp\\u003eStage\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eI\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e193\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e41,3%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e73\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e39,0%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e48\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e36,9%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e314\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e40,1%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\" morerows=\\\"2\\\" rowspan=\\\"3\\\"\\u003e \\u003cp\\u003e0.771\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e199\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e42,6%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e88\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e47,1%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e61\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e46,9%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e348\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e44,4%\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eIII\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e16,1%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e13,9%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e21\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e16,2%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e122\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e15,6%\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eHistologic Grade\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1\\u0026ndash;2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e172\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e37,1%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e35,0%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e44\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e33,8%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e280\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e36,1%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e0.738\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e291\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e62,9%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e119\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e65,0%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e86\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e66,2%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e496\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e63,9%\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eRandomization arm\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eLong\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e242\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e51,8%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e49,2%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e59\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e45,4%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e393\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e50,1%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e0.413\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eShort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e225\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e48,2%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e50,8%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e71\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e54,6%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e391\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c10\\\"\\u003e \\u003cp\\u003e49,9%\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"11\\\"\\u003eAbbreviations: n, number; tot, total; yrs, years; Q1, first quartile; Q3, third quartile; AI, aromatase inhibitor; TAM, tamoxifen\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSurvival according to type of adjuvant ET\\u003c/h2\\u003e \\u003cp\\u003eAt a median follow up of 8.7 years (95% CI 8.6\\u0026ndash;8.8), 141 out of 784 patients had a DFS event (18.0%).\\u003c/p\\u003e \\u003cp\\u003eDFS was significantly different according to the type of adjuvant ET received. At 8 years the DFS rates were: 86.4% for AI, 81.3% for TAM and 77.7% for TAM-AI (log-rank p\\u0026thinsp;=\\u0026thinsp;0.032; Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eA). Univariate cox-regression analyses with the AI group as reference showed an HR of 1.40 (95% CI 0.95\\u0026ndash;2.08, p\\u0026thinsp;=\\u0026thinsp;0.089) for TAM and an HR of 1.68 (95% CI 1.10\\u0026ndash;2.55, p\\u0026thinsp;=\\u0026thinsp;0.016) for TAM-AI. Since the AI group emerged as the one with the most favorable prognosis and patients treated with TAM or TAM-AI showed similar outcomes, we compared DFS for AI-treated vs TAM or TAM-AI-treated patients. DFS rates at 8 years were 86.4% for AI and 79.7% for TAM/TAM-AI, with an absolute difference of 6.7% (log-rank p\\u0026thinsp;=\\u0026thinsp;0.013 Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eB; HR\\u0026thinsp;=\\u0026thinsp;1.52, 95% CI 1.09\\u0026ndash;2.11, p\\u0026thinsp;=\\u0026thinsp;0.014).\\u003c/p\\u003e \\u003cp\\u003eWe conducted multivariate cox regression analyses for DFS including type of ET and other factors (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). In model 1 we included those factors that were significantly associated with DFS in univariate analysis: type of ET, stage, histologic grade. In model 2 we added menopausal status to factors included in model 1. We decided to include menopausal status since its potential confounding impact in the assessment of the effect of the type of adjuvant ET. In both models, adjuvant ET with TAM or TAM-AI was independently associated with worse DFS (HR 1.42, 95% CI 1.02\\u0026ndash;1.99, p\\u0026thinsp;=\\u0026thinsp;0.040 in model 1; HR 1.64, 95% CI 1.07\\u0026ndash;2.52, p\\u0026thinsp;=\\u0026thinsp;0.025 in model 2). In terms of OS, there was no difference according to ET received (HR 0.89, 95% CI 0.54\\u0026ndash;1.49, p\\u0026thinsp;=\\u0026thinsp;0.0667 for TAM/TAM-AI vs AI).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eUnivariate and multivariate cox-regression models for DFS.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"10\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c10\\\" colnum=\\\"10\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c4\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003eUnivariate\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c7\\\" namest=\\\"c5\\\"\\u003e \\u003cp\\u003eMultivariate model 1\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c10\\\" namest=\\\"c8\\\"\\u003e \\u003cp\\u003eMultivariate model 2\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eHR (95% CI)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ep\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eHR (95% CI)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ep\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eHR (95% CI)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ep\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c10\\\" namest=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eAI\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003eTAM or TAM-AI\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.52 (1.09\\u0026ndash;2.11)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.014\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.42 (1.02\\u0026ndash;1.99)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.040\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.64 (1.07\\u0026ndash;2.52)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.025\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c10\\\" namest=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eAge (continuous)\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1.00 (0.98\\u0026ndash;1.02)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.998\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c10\\\" namest=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eStage I\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003eStage II\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003eStage III\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.52 (1.02\\u0026ndash;2.26)\\u003c/p\\u003e \\u003cp\\u003e2.82 (1.80\\u0026ndash;4.41)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.040\\u003c/em\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cem\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.46 (0.98\\u0026ndash;2.18)\\u003c/p\\u003e \\u003cp\\u003e2.79 (1.78\\u0026ndash;4.36)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.066\\u003c/em\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cem\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.45 (0.97\\u0026ndash;2.17)\\u003c/p\\u003e \\u003cp\\u003e2.76 (1.77\\u0026ndash;4.32)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.071\\u003c/em\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cem\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c10\\\" namest=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eHistologic Grade 1\\u0026ndash;2\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003eHistologic Grade 3\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.79 (1.22\\u0026ndash;2.63)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.003\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.75 (1.19\\u0026ndash;2.58)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.004\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.77 (1.21\\u0026ndash;2.61)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.004\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c10\\\" namest=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eLong arm\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003eShort arm\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.08 (0.78\\u0026ndash;1.50)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.655\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e-\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e-\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c10\\\" namest=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003ePostmenopausal status\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003ePremenopausal status\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e1.17 (0.84\\u0026ndash;1.63)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.369\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e-\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e-\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c8\\\" namest=\\\"c7\\\"\\u003e \\u003cp\\u003eRef\\u003c/p\\u003e \\u003cp\\u003e0.80 (0.51\\u0026ndash;1.23)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0.303\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c10\\\" namest=\\\"c10\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"10\\\"\\u003eAbbreviations: AI, aromatase inhibitor; TAM, tamoxifen; HR, hazard ratio; CI, confidence interval; p, p value; Ref, reference.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eWe explored the annual hazard rates of DFS event in order to assess the benefit of AI over time. We excluded TAM-AI treatment from this analysis since this group included both patients switching from TAM to AI and the inverse sequence. As shown in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e, the annual hazard rate of DFS event for patients treated with AI were lower as compared to TAM at almost all timepoints considered, suggesting benefit from AI on both early and late events. However, the duration of ET beyond 5 years was unknown, limiting the interpretation of these results.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePremenopausal patients\\u003c/h2\\u003e \\u003cp\\u003eWe conducted exploratory analyses in the subgroup of 309 patients in premenopausal status at study entry based on the use of GnRHa as part of adjuvant ET. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e summarizes patients\\u0026rsquo; characteristics according to GnRHa use.\\u003c/p\\u003e \\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u0026nbsp;\\u003ctable border=\\\"1\\\" id=\\\"Tab3\\\"\\u003e\\n \\u003ccaption language=\\\"En\\\"\\u003e\\n \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e\\n \\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n \\u003cp\\u003ePatients\\u0026rsquo; characteristics according to GnRHa use in the premenopausal subgroup.\\u003c/p\\u003e\\n \\u003c/div\\u003e\\n \\u003c/caption\\u003e\\n \\u003cthead\\u003e\\n \\u003ctr\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"4\\\"\\u003e\\n \\u003cp\\u003eGnRHa use: NO, n\\u0026thinsp;=\\u0026thinsp;136\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"4\\\"\\u003e\\n \\u003cp\\u003eGnRHa use: YES, n\\u0026thinsp;=\\u0026thinsp;173\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"4\\\"\\u003e\\n \\u003cp\\u003eTotal\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eP\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/thead\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003en\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003en\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003en\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\"\\u003e\\n \\u003cp\\u003eAge\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eYears, median (Q1; Q3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"4\\\"\\u003e\\n \\u003cp\\u003e49 (46; 51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"4\\\"\\u003e\\n \\u003cp\\u003e43 (39; 46)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"4\\\"\\u003e\\n \\u003cp\\u003e46 (41; 49)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" rowspan=\\\"3\\\"\\u003e\\n \\u003cp\\u003eStage\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e61\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e44,9%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e70\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e40,5%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e131\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e42,4%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eII\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e54\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e39,7%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e78\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e45,1%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e132\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e42,7%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eIII\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e21\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e15,4%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e25\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e14,5%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e46\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e14,9%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e0.634\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" rowspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eHistologic Grade\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e1\\u0026ndash;2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e39\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e28,9%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e60\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e35,5%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e99\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e32,6%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e96\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e71,1%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e109\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e64,5%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e205\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e67,4%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e0.221\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" rowspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eEndocrine therapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eAI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e55\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e40,4%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e4,0%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e62\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e20,1%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eTAM or TAM-AI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e81\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e59,6%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e166\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e96,0%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e247\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e79,9%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" rowspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eTreatment arm\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eLong\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e69\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e50,7%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e83\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e48,0%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e152\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e49,2%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003eShort\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e67\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e49,3%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e90\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e52,0%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e157\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e50,8%\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\"\\u003e\\n \\u003cp\\u003e0.630\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n \\u003ctfoot\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd colspan=\\\"17\\\"\\u003eAbbreviations: GnRH, gonadotropin-releasing hormone; p, p value; Q1, first quartile; Q3, third quartile; AI, aromatase inhibitor; TAM, tamoxifen\\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tfoot\\u003e\\n \\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003e\\u003cbr\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eMore than half of patients (56.0%, n\\u0026thinsp;=\\u0026thinsp;173) received GnRHa as part of the adjuvant ET. These patients, as compared to those who did not undergo GnRH treatment, were significantly younger (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). Almost all patients (96%) undergoing GnRHa received TAM or TAM-AI vs 59.6% not receiving GnRHa (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). This apparently counterintuitive result was driven by 55 patients who received AI without GnRHa. This group likely included perimenopausal patients who achieved an effective OFS following chemotherapy for whom clinicians opted for an AI without GnRHa with close monitoring of FSH, LH and estradiol levels. This hypothesis is supported by the median age of this subgroup of patients (premenopausal at study entry, no GnRHa use, treated with AI): 51 years, Q1:48; Q3: 53. In order to avoid potential confounding factors, we explored the impact of GnRHa on DFS by including only premenopausal patients aged\\u0026thinsp;\\u003cspan class=\\\"Underline\\\" name=\\\"Emphasis\\\" type=\\\"Underline\\\"\\u003e\\u0026le;\\u003c/span\\u003e\\u0026thinsp;45 years (n\\u0026thinsp;=\\u0026thinsp;147). In this group, 20% of patients did not receive GnRHa, 97% received TAM or TAM-AI, only 4 patients received AI (combined with GnRHa). As shown in Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e, GnRHa was associated with improved outcome: DFS rates at 8 years were 85.2% vs 62.6%, log-rank p\\u0026thinsp;=\\u0026thinsp;0.019 (HR 0.41, 95% CI 0.19\\u0026ndash;0.88, p\\u0026thinsp;=\\u0026thinsp;0.023).\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this work, we show that adjuvant ET with AI is superior to TAM or TAM-AI in terms of DFS for patients with HR-positive/HER2-positive BC receiving adjuvant anthracycline/taxane-based chemotherapy combined with trastuzumab. These results derive from an exploratory analysis of a randomized trial with 8.7 years of median follow up. Conflicting results exist about a potential detrimental effect of HER2 overexpression on TAM efficacy[\\u003cspan additionalcitationids=\\\"CR26\\\" citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e] and our data add to the ongoing debate about optimal adjuvant ET for patients with HR-positive/HER2-positive BC. The EBCTCG metanalysis did not demonstrate any interaction between HER2 status and benefit from AI over TAM in postmenopausal patients[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. However, a recent trial-level metanalysis addressing this clinical question provided contradictory findings. This study included 5,390 HR-positive/HER2-positive BC patients (of whom 2,410 in premenopausal status) from 6 randomized trials: 5 trials of adjuvant ET (TEAM, ATAC, BIG 1\\u0026ndash;98, TEXT and SOFT) and 1 trial of adjuvant anti-HER2-therapy (ALTTO)[\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. The results showed no difference in DFS between adjuvant treatment with AI and TAM[\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. This metanalysis has several limitations. The number of HR-positive/HER2-positive BC patients in most of these studies was small (in the range of 6 to 12%, excluding ALTTO) and HER2 status was not available for a large proportion of patients. Moreover, trastuzumab adjuvant treatment was administered to a minority of patients in the TEAM, ATAC and BIG 1\\u0026ndash;98 trials, and only to 60% of HR-positive/HER2-positive BC patients from the TEXT and SOFT trials. In addition, the TEAM, ATAC and BIG 1\\u0026ndash;98 results apply only to treatment and events occurring in the first 2\\u0026ndash;3 years of adjuvant ET.\\u003c/p\\u003e \\u003cp\\u003eConversely, our analysis is based on a randomized trial dedicated to HER2-positive BC patients, includes a large number of cases with HR-positive/HER2-positive BC (n\\u0026thinsp;=\\u0026thinsp;784), all treated with standard adjuvant chemotherapy and trastuzumab. The type of ET was collected for the first 5 years of follow up, median follow-up is long (8.7 years) and survival analysis refers to DFS events occurring throughout the follow up period.\\u003c/p\\u003e \\u003cp\\u003eThe superiority of AI demonstrated in our work is consistent with the results of a post-hoc analysis from the ALTTO trial. This analysis shows similarities with our work, since it included a large subgroup of HR-positive/HER2-positive BC patients (3,603, of whom 1,888 premenopausal) from a clinical trial dedicated to HER2-positive BC patients all treated with adjuvant anti-HER2 therapy[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. In multivariate analysis, AI was associated with better DFS as compared to TAM (HR 0.70, 95% CI 0.57\\u0026ndash;0.97)[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. Differently to our findings, also TAM-AI was associated with improved DFS as compared to TAM (HR 0.45, 95% CI 0.33\\u0026ndash;0.61)[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. Differences in the classification of the type of ET might have impacted this discrepant finding. In our study we define TAM-AI treatment when each drug was administered for at least 1 year. No information on the methods applied to categorize TAM-AI treatment is available for the ALTTO analysis. Moreover, a slightly higher proportion of postmenopausal patients is included in our cohort (60.7% vs 52.4% in ALTTO). Another difference is the very limited use of OFS in the ALTTO trial (\\u0026lt;\\u0026thinsp;1% of the study population).\\u003c/p\\u003e \\u003cp\\u003eCumulative evidence suggests that the benefit from AI over TAM in HR-positive/HER2-positive BC patients may be dependent on menopausal status. Despite we show an association with improved DFS for the use of AI over TAM/TAM-AI that is independent from menopausal status in multivariate analysis, our data should be considered more informative for postmenopausal or perimenopausal patients and less informative for true premenopausal patients. Our population includes a large proportion of postmenopausal patients and, among those defined as premenopausal at study entry, there were probably patients in perimenopausal status who achieved effective OFS following chemotherapy. In addition, only few premenopausal patients aged\\u0026thinsp;\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003e\\u0026le;\\u003c/span\\u003e\\u0026thinsp;45 years received AI, therefore conclusions about the optimal adjuvant ET for premenopausal patients can not be drawn based on our results.\\u003c/p\\u003e \\u003cp\\u003eIn the TEXT and SOFT trials, for patients undergoing OFS, TAM was numerically superior to AI in the subgroup of HER2-positive BC patients[\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. The recent EBCTCG metanalysis comparing AI vs TAM in the context of OFS for premenopausal patients also suggested greater benefit from AI vs TAM in HER2-negative disease than in HER2-positive disease (RR 0\\u0026middot;65 \\u003cem\\u003evs\\u003c/em\\u003e 1\\u0026middot;08, p\\u0026thinsp;=\\u0026thinsp;0\\u0026middot;021)[\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]. However, the HER2-positive subgroup was limited in sample size with a small number of events. Moreover, the difference between HER2-positive and HER2-negative tumors did not reach statistical significance[\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]. A population-based cohort study from the Netherlands Cancer Registry including 1,155 HR-positive/HER2-positive BC patients reported a significant benefit from AI over TAM in perimenopausal patients (age\\u0026thinsp;\\u0026lt;\\u0026thinsp;45 to \\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003e\\u0026le;\\u003c/span\\u003e\\u0026thinsp;55 years as a proxy), a numerical benefit in postmenopausal patients (age\\u0026thinsp;\\u0026gt;\\u0026thinsp;55 years), and a lack of benefit for premenopausal patients (age\\u0026thinsp;\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003e\\u0026le;\\u003c/span\\u003e\\u0026thinsp;45 years)[\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. Limitations of this analysis are: the heterogeneous administration of adjuvant trastuzumab, the heterogeneous use of OFS for premenopausal patients, and the lack of a clinical definition of menopausal status. However, these findings further support the hypothesis that hormonal microenvironment changes may affect the efficacy of ET in HR+/HER2\\u0026thinsp;+\\u0026thinsp;BC patients.\\u003c/p\\u003e \\u003cp\\u003eA final keypoint of our work is the exploratory analysis on the role of OFS for premenopausal patientsThe addition of GnRHa to ET (mainly TAM or TAM-AI) for premenopausal patients aged\\u0026thinsp;\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003e\\u0026le;\\u003c/span\\u003e\\u0026thinsp;45 years was associated with a significantly better DFS. Subgroup analyses of the SOFT trial demonstrated improved outcome for OFS added to TAM in HER2-positive disease[\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. The Dutch population-based cohort study also described a survival benefit when OFS was added to ET for HR+/HER2\\u0026thinsp;+\\u0026thinsp;BC patients[\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. In this work, we demonstrate for the first time the benefit of OFS in the context of a randomized trial including patients all treated with adjuvant chemotherapy and trastuzumab. The low rate GnRHa use in the ALTTO trial limits the possibility to explore this issue in that study[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. It has to be noticed that the duration of GnRHa administration was not systematically collected. At the time the trial was conducted the optimal duration of OFS was unknown and OFS was generally administered for 2\\u0026ndash;5 years[\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eOur study has limitations. First, this is an unplanned post-hoc analysis. Second, it was not possible to properly assess therapy duration beyond 5 years and treatment adherence/interruptions. Moreover, perimenopausal patients were not clearly defined and other means of OFS beyond GnRHa were not captured after screening.\\u003c/p\\u003e \\u003cp\\u003eIn conclusion, our findings support the use of AI as adjuvant therapy for HR-positive/HER2-positive BC patients in the context of standard adjuvant treatment including chemotherapy and trastuzumab. In premenopausal patients, the use of OFS prolongs DFS. However, the optimal endocrine oral therapy (either AI or TAM) in this subgroup remains unclear and warrants further evaluation in large cohorts of patients treated with standard adjuvant therapy.\\u003c/p\\u003e\"},{\"header\":\"List Of Abbreviations\",\"content\":\"\\u003cp\\u003eBC, breast cancer; AI, aromatase inhibitor; TAM, tamoxifen; ET, endocrine therapy; HR, hormone receptor positive; HER2, human epidermal growth factor receptor 2; DFS, disease-free survival; OS, overall survival, GnRHa, gonadotropin-releasing hormone analogues; OFS, ovarian function suppression.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate:\\u0026nbsp;\\u003c/strong\\u003eThe trial was approved by local ethical Committees of all participating centers, and conducted in compliance with the principles of Good Clinical Practice and the Declaration of Helsinki. All patients signed an informed consent form.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials:\\u0026nbsp;\\u003c/strong\\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication:\\u003c/strong\\u003e not applicaple\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests:\\u0026nbsp;\\u003c/strong\\u003eMVD reports personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Seagen, Gilead, MSD, AstraZeneca, Daiichi Sankyo outside the submitted work. AF reports personal fees from Roche, Novartis, EliLilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, outside the submitted work. PFC reports personal fees from Novartis, EliLilly, AstraZeneca, Tesaro, Daiichi-Sankyo, Gilead, reveal Genomics, BMS, Roche outside the submitted work. VG reports personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Gilead, MSD, Amgen, Sanofi, Merck Serono, Eisai outside the submitted work.\\u0026nbsp;The other authors declare no conflict of interest.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding:\\u0026nbsp;\\u003c/strong\\u003eThis work was supported by Agenzia Italiana del Farmaco (AIFA, grant FARM62MC97),\\u0026nbsp;Italian Association for Cancer Research (AIRC, project MFAG 2014 – 15938; to V. Guarneri),\\u0026nbsp;funding from the University of Padova—Department of Surgery, Oncology and Gastroenterology DOR 2019 (to V.G., M.V.D., P.F.C.), DOR 2020 (to V.G., M.V.D.), DOR 2021 (M.V.D., G.G.); Fondazione AIRC under 5 per mille 2019 (ID. 22759 program— group leader V.G.),\\u0026nbsp;Ricerca\\u0026nbsp;Corrente funding from the Italian Ministry of Health.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors' contributions:\\u0026nbsp;\\u003c/strong\\u003eMVD: conceptualization, data curation, formal analysis, investigation, writing-original draft; GB, SB, AF: data curation, investigation, writing – review \\u0026amp; editing; RV: data curation, software, writing – review \\u0026amp; editing; SB, RDA: data curation, formal analysis, methodology, writing – review \\u0026amp; editing; PFC: supervision, investigation, funding acquisition, writing – review \\u0026amp; editing; VG: conceptualization, supervision, investigation, funding acquisition, writing – review \\u0026amp; editing.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments:\\u0026nbsp;\\u003c/strong\\u003enot applicable\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eCort\\u0026eacute;s J, Saura C, Bellet M, Mu\\u0026ntilde;oz-Couselo E, Ram\\u0026iacute;rez-Merino N, Calvo V, et al. HER2 and hormone receptor-positive breast cancer\\u0026mdash;blocking the right target. Nat Rev Clin Oncol. 2011;8:307\\u0026ndash;11.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61\\u0026ndash;70.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDieci MV, Conte P, Bisagni G, Brandes AA, Frassoldati A, Cavanna L, et al. Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2 + breast cancer. Annals of Oncology. 2019;30:418\\u0026ndash;23.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDieci MV, Guarneri V. Should triple-positive breast cancer be recognized as a distinct subtype? Expert Rev Anticancer Ther. 2020;20:1011\\u0026ndash;4.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, et al. 11 years\\u0026rsquo; follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. The Lancet. 2017;389:1195\\u0026ndash;205.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLambertini M, Campbell C, Gelber RD, Viale G, McCullough A, Hilbers F, et al. Dissecting the effect of hormone receptor status in patients with HER2-positive early breast cancer: exploratory analysis from the ALTTO (BIG 2\\u0026ndash;06) randomized clinical trial. Breast Cancer Res Treat. 2019;177:103\\u0026ndash;14.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. The Lancet. 2014;384:164\\u0026ndash;72.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGuarneri V, Dieci MV, Frassoldati A, Maiorana A, Ficarra G, Bettelli S, et al. Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer. Oncologist. 2015;20:1001\\u0026ndash;10.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMoja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database of Systematic Reviews. 2012;2021.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eChumsri S, Li Z, Serie DJ, Mashadi-Hossein A, Colon-Otero G, Song N, et al. Incidence of Late Relapses in Patients With HER2-Positive Breast Cancer Receiving Adjuvant Trastuzumab: Combined Analysis of NCCTG N9831 (Alliance) and NRG Oncology/NSABP B-31. Journal of Clinical Oncology. 2019;37:3425\\u0026ndash;35.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBenz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, et al. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat. 1992;24:85\\u0026ndash;95.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDowsett M, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, et al. Biomarker Changes During Neoadjuvant Anastrozole, Tamoxifen, or the Combination: Influence of Hormonal Status and HER-2 in Breast Cancer\\u0026mdash;A Study from the IMPACT Trialists. Journal of Clinical Oncology. 2005;23:2477\\u0026ndash;92.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEllis MJ, Tao Y, Young O, White S, Proia AD, Murray J, et al. Estrogen-Independent Proliferation Is Present in Estrogen-Receptor \\u003cem\\u003eHER2\\u003c/em\\u003e -Positive Primary Breast Cancer After Neoadjuvant Letrozole. Journal of Clinical Oncology. 2006;24:3019\\u0026ndash;25.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDowsett M, Harper-Wynne C, Boeddinghaus I, Salter J, Hills M, Dixon M, et al. HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer. Cancer Res. 2001;61:8452\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRimawi M, Ferrero J-M, de la Haba-Rodriguez J, Poole C, de Placido S, Osborne CK, et al. First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2\\u0026ndash;Positive and Hormone Receptor\\u0026ndash;Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial. Journal of Clinical Oncology. 2018;36:2826\\u0026ndash;35.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJohnston SRD, Hegg R, Im S-A, Park IH, Burdaeva O, Kurteva G, et al. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor\\u0026ndash;Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. Journal of Clinical Oncology. 2021;39:79\\u0026ndash;89.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2019;30:1194\\u0026ndash;220.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBradley R, Braybrooke J, Gray R, Hills RK, Liu Z, Pan H, et al. Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 2022;23:382\\u0026ndash;92.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBartlett JMS, Ahmed I, Regan MM, Sestak I, Mallon EA, Dell\\u0026rsquo;Orto P, et al. HER2 status predicts for upfront AI benefit: A TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1\\u0026ndash;98 and TEAM with centrally determined HER2. Eur J Cancer. 2017;79:129\\u0026ndash;38.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFrancis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, L\\u0026aacute;ng I, et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. New England Journal of Medicine. 2018;379:122\\u0026ndash;37.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGuarneri V, Frassoldati A, Bruzzi P, D\\u0026rsquo;Amico R, Belfiglio M, Molino A, et al. Multicentric, Randomized Phase III Trial of Two Different Adjuvant Chemotherapy Regimens plus Three Versus Twelve Months of Trastuzumab in Patients with HER2-Positive Breast Cancer (Short-HER Trial; NCT00629278). Clin Breast Cancer. 2008;8:453\\u0026ndash;6.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eConte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, et al. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. Annals of Oncology. 2018;29:2328\\u0026ndash;33.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLinee Guida Neoplasie della Mammella AIOM 2013. Available at \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://media.aiom.it/userfiles/files/doc/LG/2013_LG_AIOM_Mammella_V_101013.pdf\\u003c/span\\u003e\\u003cspan address=\\\"http://media.aiom.it/userfiles/files/doc/LG/2013_LG_AIOM_Mammella_V_101013.pdf\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e. 2013.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOrtmann O, Pagani O, Jones A, Maass N, Noss D, Rugo H, et al. Which factors should be taken into account in perimenopausal women with early breast cancer who may become eligible for an aromatase inhibitor? Recommendations of an expert panel. Cancer Treat Rev. 2011;37:97\\u0026ndash;104.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ede Placido S, de Laurentiis M, Carlomagno C, Gallo C, Perrone F, Pepe S, et al. Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer. Clin Cancer Res. 2003;9:1039\\u0026ndash;46.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eElledge RM, Green S, Ciocca D, Pugh R, Allred DC, Clark GM, et al. HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study. Clin Cancer Res. 1998;4:7\\u0026ndash;12.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDowsett M, Allred C, Knox J, Quinn E, Salter J, Wale C, et al. Relationship Between Quantitative Estrogen and Progesterone Receptor Expression and Human Epidermal Growth Factor Receptor 2 (HER-2) Status With Recurrence in the Arimidex, Tamoxifen, Alone or in Combination Trial. Journal of Clinical Oncology. 2008;26:1059\\u0026ndash;65.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePeleg Hasson S, Brezis MR, Shachar E, Shachar SS, Wolf I, Sonnenblick A. Adjuvant endocrine therapy in HER2-positive breast cancer patients: systematic review and meta-analysis. ESMO Open. 2021;6:100088.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBradley R, Braybrooke J, Gray R, Hills RK, Liu Z, Pan H, et al. Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 2022;23:382\\u0026ndash;92.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDackus GMHE, J\\u0026oacute;źwiak K, Sonke GS, van der Wall E, van Diest PJ, Hauptmann M, et al. Optimal adjuvant endocrine treatment of ER+/HER2 + breast cancer patients by age at diagnosis: A population-based cohort study. Eur J Cancer. 2018;90:92\\u0026ndash;101.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSenkus E, Kyriakides S, Penault-Llorca F, Poortmans P, Thompson A, Zackrisson S, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2013;24:vi7\\u0026ndash;23.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"HER2-positive, aromatase inhibitor, tamoxifen, ovarian function suppression, adjuvant\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-2063715/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-2063715/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eWe evaluated the impact of the type of endocrine therapy on disease-free survival (DFS) in patients with HR-positive/HER2-positive BC enrolled in the phase III ShortHER trial.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eShort-HER randomized 1254 patients with HER2-positive early BC to 9 weeks vs 1 year of adjuvant trastuzumab combined with anthracycline-taxane chemotherapy. The type of adjuvant endocrine was collected during the first 5 years of follow-up and was classified as: aromatase inhibitor (AI), tamoxifen and aromatase inhibitor (TAM-AI), or tamoxifen (TAM). The use of gonadotropin-releasing hormone analogues (GnRHa) was also collected. DFS was calculated from randomization to disease recurrence, second primary tumor, or death.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003e784 patients with HR-positive BC were included: 60.5% postmenopausal, median age 55 years. The pattern of endocrine therapy was: 59.6% AI, 23.8% TAM, 16.6% TAM-AI. At a median follow up of 8.7 years, patients who received AI had a significantly better DFS vs patients who received TAM or TAM-AI: 8-yr DFS 86.4% vs 79.7%, log-rank P\\u0026thinsp;=\\u0026thinsp;0.013 (HR 1.52, 95%CI 1.09\\u0026ndash;2.11). In multivariate analysis, the type of endocrine therapy maintained a significant association with DFS (HR 1.64, 95% CI 1.07\\u0026ndash;2.52, p\\u0026thinsp;=\\u0026thinsp;0.025 for TAM/TAM-AI vs AI). Among premenopausal patients aged\\u0026thinsp;\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003e\\u0026le;\\u003c/span\\u003e\\u0026thinsp;45 years (97% receiving TAM or TAM-AI), the use of GnRHa was associated with longer DFS: 8-yr DFS rate 85.2% vs 62.6% (log-rank p\\u0026thinsp;=\\u0026thinsp;0.019, HR 0.41, 95% CI 0.19\\u0026ndash;0.88).\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003eIn this post-hoc analysis of the ShortHER trial adjuvant treatment with AI was independently associated with improved DFS. Subgroup analysis in young premenopausal patients suggests benefit with ovarian suppression.\\u003c/p\\u003e\\u003ch2\\u003eTrial registration:\\u003c/h2\\u003e \\u003cp\\u003eNCI ClinicalTrials.gov number: NCT00629278. Registered 5 March 2008. Retrospectively registered (first patient in December 2007).\\u003c/p\\u003e\",\"manuscriptTitle\":\"Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2022-09-23 14:27:54\",\"doi\":\"10.21203/rs.3.rs-2063715/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"f3d74980-2dee-4613-a280-beae88a426be\",\"owner\":[],\"postedDate\":\"September 23rd, 2022\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2022-09-23T14:27:55+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2022-09-23 14:27:54\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-2063715\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-2063715\",\"identity\":\"rs-2063715\",\"version\":[\"v1\"]},\"buildId\":\"0shC4O-rRljfh4Nq9OyMh\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}