Management of the axilla in postmenopausal patients with cN0 hormone receptor-positive/ HER2-negative breast cancer treated with neoadjuvant endocrine therapy and its prognostic impact.

Management of the axilla in postmenopausal patients with cN0 hormone receptor-positive/ HER2-negative breast cancer treated with neoadjuvant endocrine therapy and its prognostic impact. | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Management of the axilla in postmenopausal patients with cN0 hormone receptor-positive/ HER2-negative breast cancer treated with neoadjuvant endocrine therapy and its prognostic impact. Amparo Garcia-Tejedor, Sergi Fernandez-Gonzalez, Maria Laplana, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2394671/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Apr, 2023 Read the published version in Breast Cancer Research and Treatment → Version 1 posted 6 You are reading this latest preprint version Abstract Purpose To evaluate the differences when performing the sentinel lymph node biopsy (SLNB) before or after neoadjuvant endocrine therapy (NET) in breast cancer patients, and the impact of its timing on prognosis. Methods A retrospective cohort study including 91 postmenopausal cases with clinically node-negative and hormone receptor-positive/HER2 negative (HR+/HER2-) breast cancer, treated with NET and SLNB at our institution. SLNB was performed pre-NET until 2014, and post-NET thereafter. Axillary lymph node dissection (ALND) was indicated only in SLNB-macrometastasis, although in selected elderly patients it was omitted. Kaplan-Meier survival curves were obtained in relation to the status of the axilla, and the differences assessed using the log-rank test. Results Between December 2006 and March 2022, SLNB was performed pre-NET in 14 cases and post-NET in 77. SLNB-positivity was similar regardless of whether SLNB was performed before or after NET (35.7% and 37%, respectively), with 2/14 SLN macrometastases in the pre-NET cohort and 17/77 in the post-NET cohort. Only three patients (18.7%) with SLN macrometastasis had > 3 positive nodes following axillary node dissection. The 5-year overall survival and distant disease-free survival were 92.4% and 94.8% respectively, with no significant differences according to SLNB status. Conclusion SLN positivity did not differ according to its timing (before or after NET). Therefore, NET has no effect on lymph node clearance. Furthermore, the prognosis is good regardless of the axillary involvement. Therefore, factors other than axillary involvement may affect the prognosis in these patients. Neoadjuvant endocrine therapy sentinel lymph node biopsy hormone-receptor-positive breast cancer axillary management axillary node dissection de-escalation Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors are the most common type of breast cancer, accounting for approximately 70% of cases. This subgroup of tumors has a better prognosis than others and is less sensitive to chemotherapy, and so requires different therapeutic approaches. In contrast, the axillary management of these patients does not differ from that applied in other more aggressive subtypes. Several clinical trials have demonstrated that neoadjuvant endocrine therapy (NET) in postmenopausal patients can downsize HR+/HER2- tumors and facilitate breast-conserving surgery 1 . Aromatase inhibitors are the treatment of choice 2 . However, axillary management strategies are underreported in these patients; indeed, they have been excluded not just from the large trials evaluating the feasibility of sentinel lymph node biopsy (SLNB) after preoperative therapy 3 but also from most of the ongoing clinical trials investigating regional nodal radiation after positive SLNB and neoadjuvant systemic therapy (NST). As a result, information on axillary management in the NET setting is lacking. Neoadjuvant chemotherapy (NAC) has been shown to reduce the requirement for axillary lymph node dissection (ALND) in clinically node-positive (cN+) patients, since it achieves a complete pathological axillary response (pCR) in more than 60% of cases, especially for HER2-positive and triple negative tumors 4 , 5 . By contrast, the incidence of axillary pCR after NET is much lower (< 10%) 6 . Moreover, in node-negative (cN0) disease, ALND rates also fell from 42% when performed before NAC to 12% following NAC 7 , thanks to the downstaging of the undetectable lymph nodes involved. However, no data on SLNB before or after NET were reported. The lack of significant differences in survival outcomes observed in patients aged ≥ 60 years with HR+/HER2- disease treated with or without ALND 8 suggests an opportunity to de-escalate treatment when patients have limited residual nodal disease. In fact, information from the National Cancer Database after examining patterns of axillary management in patients with cN0 HR+/HER2- disease revealed that those who had a positive SLNB after NET were less likely to complete ALND, thus favoring the adoption of less aggressive management strategies by this group 9 . Nevertheless, the long-term impact of omitting ALND in this setting remains unknown. The efficacy and tolerability of NET have been widely reported, especially in elderly patients, and its superior cost-efficacy balance compared with NAC has been stressed. However, it is not widely used in clinical practice 10 . Given the limited data available for axillary management after NET, the present study aimed to evaluate the differences in performing the SLNB before or after NET in patients with cN0 HR+/HER2- breast cancer, as well as its impact on adjuvant chemotherapy decision-making and prognosis. Material And Methods Study design and patients This retrospective cohort study of a prospectively maintained database included cN0 breast cancer patients treated with NET at Institut Català d’Oncologia-Hospital Universitari Bellvitge, between December 2006 and March 2022. In that period, 522 patients were identified as candidates for NST, and 91 were finally treated with NET (17.4%) (see Fig. 1 ). The Hospital Universitari Bellvitge Institutional Review Board approved the study (247/06), and all patients signed informed consent forms. The anonymization of all patient data was ensured, and their confidential information protected in accordance with the national regulations. Patients were required to meet all the following eligibility criteria: (1) postmenopausal women, or men; (2) palpable breast tumor; (3) clinical and radiological cN0 at diagnosis (by axillary ultrasound); (4) invasive breast carcinoma in tumor core biopsy, estrogen receptor (ER) > 50% and HER2-negative tumors; (5) NET; and (6) willingness to undergo surgery following NET. We excluded patients who had ALN-positive disease at diagnosis by fine-needle aspiration, NAC, and HER2-positive tumors. Treatments and cohorts NET was indicated in patients with HR+/HER2- palpable breast tumor according to our multidisciplinary committee. Treatment consisted of 2.5 mg letrozole in women and 20 mg tamoxifen in men for 6–12 months, depending on response. Conservative or radical breast surgery following NET was decided according to tumor response, tumor size, and predictable aesthetic results. Cases were distributed into two cohorts based on when they underwent SLNB before (pre-NET) and after NET (post-NET). SLNB was performed before NST from December 2006 to April 2014 and following NST thereafter according to our breast cancer guidelines. Peritumor injection of 3 mCi/mL 99m-technetium radiocolloid (99m-Tc) was administered for lymphatic mapping 24 hours before the SLNB. When initial migration had not been observed on a previous gammagraphic map, we performed a second injection with 99m-Tc the day before to improve migration. Radioactivity was detected with an intraoperative gamma probe (Europrobe; Britec, Sheffield, United Kingdom). In the pathology department, the SLN and adipose tissue were fixed in 10% formaldehyde and completely embedded in paraffin, and processed in 3-mm sections, separated by 150 mm, three stained using hematoxylin and eosin and three stained using AE1/AE3 cytokeratin. Micrometastasis was defined as a small cluster of cells measuring 0.2–2 mm, and macrometastasis as > 2 mm. In both cohorts, deferred ALND was performed in patients with SLNB macrometastasis, except in selected elderly women in whom it was omitted in accordance with the Rudenstam et al. guidelines 8 . Patients with negative SLNs or with SLN micrometastasis did not undergo further treatment of the axilla. Adjuvant chemotherapy was offered to patients with a postoperative endocrine prognostic index 11 (PEPI score) > 3 if they were aged < 80 years and had a good performance status (< 2). Most of the schemas included taxanes; however, therapy was adapted to each patient depending on their associated comorbidities prior to oncogeriatric screening. All patients received the same adjuvant endocrine therapy as in the neoadjuvant setting (2.5 mg letrozole, except in cases of progression during NET) to complete a minimum of five years. All patients had radiotherapy of the breast or chest wall according to our institutional guidelines after breast-conserving surgery and in cases with cT3-T4 tumors after mastectomy. Patients with SLNB-positive disease also received supraclavicular radiotherapy, including level III-ALN. Variables We recorded the following clinical and pathologic variables: age, tumor size before and after NET, histological type, Nottingham histological grade, lymphovascular invasion, hormonal receptors status, proliferative index by Ki-67 staining, percentage of TILs (considered negative if < 5% of stromal TILs), treatment duration, type of breast and axillary surgery, SLN identification rate, SLN involvement, ALND rate, and any adjuvant treatments. Samples were divided into two surrogate subtypes according to PR and Ki-67 expression 12 : Luminal A-like, for progesterone receptor (PR) > 20%, and Ki-67 < 20%; and Luminal B-like (HER2-), for PR 20%. The Ki-67 proliferative index was grouped as > 30% or 10% or < 10% after NET. Evaluation of clinical and radiological responses was grouped according to World Health Organization criteria, as complete response, partial response, no response, or progression 13 . Pathological complete response was considered when the pathologist observed 100% fibrosis replacing the invasive carcinoma and no axillary involvement, partial response if > 30% of fibrosis, and no response if < 30% fibrosis. Follow-up The patients were evaluated clinically and radiologically every three months before surgery. Radiological assessment included mammography and ultrasound of the breast and axilla in all cases, with magnetic resonance imaging reserved for selected cases. After surgery, patients were followed clinically every six months, with an annual mammography. Recurrences were defined as local when present in the ipsilateral breast or lymph nodes and systemic when they involved contralateral lymph nodes or other organs. Contralateral tumors were recorded separately. Statistical analysis Categorical variables are presented as the number of cases and proportions, whereas normally distributed continuous variables are presented as means and standard deviations (SD). Differences between the pre-NET and post-NET groups were analyzed by the chi-square test or Fisher’s exact test for categorical variables and by the Student t-test for continuous variables. The level of statistical significance was arbitrarily set at 5%. Statistical analyses were performed using IBM SPSS version 23.0 (IBM Corp., Armonk, NY, USA). Distant disease-free survival (DDFS) was defined as the time from diagnosis to distant recurrence, a second primary invasive cancer, or death from any cause. Breast cancer specific survival (BCSS) was calculated from diagnosis until death from breast cancer, and overall survival (OS) was calculated from diagnosis until death from any cause. OS, BCSS, and DDFS were calculated at 5 years with their 95% confidence intervals (95%CIs). Kaplan–Meier survival curves of DDFS and OS were obtained in relation to the status of the axilla, which was grouped as ypN0 or ypN+, to assess the impact of affected lymph nodes in the context of HR + HER2- tumors, and the differences were computed by the log-rank test. Patients without events were censored at the time of the last follow-up. Results From December 2006 to March 2022, we included 89 patients who underwent NET and SLNB (88 women and 1 man); two of the patients had bilateral synchronous disease, so the final sample comprised 91 cases. SLNB was performed before NET in 14 cases (pre-NET cohort) and following NET in 77 (post-NET cohort). Table 1 shows the baseline characteristics of the patients and tumors, as well as the clinical-radiological response in the overall sample. The seven cT1N0 cases included were due to bilateral tumors (n = 1), comorbidity associated with the diagnosis (n = 4), or COVID infection requiring surgical delay (n = 2). Mammographic evaluation of a breast tumor before and after NET, with partial response, is shown in Fig. 2 . Table 1 Patient and tumor characteristics* Mean (SD) Nº of patients (%) Age, years 69.5 (7.9) cT 1 2 3 4 7 (7.7%) 57 (62.6%) 20 (22%) 7 (7.7%) Tumor size, mm** 39.8 (20) Histology No special type (Ductal) Lobular Other 64 (70.3%) 25 (27.5%) 2 (2.2%) Nottingham histological grade 1 2 3 Not evaluable 26 (28.6%) 58 (63.7%) 6 (6.6%) 1 (1.1%) Ki-67 ≤ 30% > 30% 80 (87.9%) 11 (12.1%) Molecular surrogate subtype Luminal A-like Luminal B-like 39 (42.9%) 52 (57.1%) Vascular invasion Yes No Missing 0 (0%) 70 (76.9%) 21 (23.1%) TILs Positive Negative Missing 16 (17,6%) 52 (57.1%) 23 (25.3%) Clinical-radiological response Complete Partial > 50% No response Progression 6 (6.6%) 73 (80.2%) 11 (12.1%) 1 (1.1%) Abbreviations: SD, standard deviation; %, percentage of patients; TILs, tumor-infiltrating lymphocytes * Data related to 91 tumours in 89 patients. **Tumor size measured by magnetic resonance imaging in 58 cases and ultrasounds in 33. SLNB identification rate was higher before NET: 100% versus 94.5% after NET (Table 2 ). In three of the four undetectable cases, ALND was omitted because the patients were elderly. SLNB positivity was similar whether performed before or after NET (35.7% versus 37% respectively) and the rate of omission of ALND was similar in the two cohorts (85.7% pre-NET and 88.2% post-NET). Note that only three of the 17 ALND performed (17.6%) had > 3 positive nodes in the final pathology report, and that all these cases had more than one positive SLNB. Table 2. Outcomes of axillary surgery Pre-NET (n = 14) Post-NET (n=77) p SLN Identification Rate (%) 14 (100%) 73 (94.8%) 1 SLN removed, mean (SD) 1.7 (0.9) 1.8 (0.9) 0.85 SLN pathological result Positive Negative 5 (35.7%) 9 (64,3%) 27 (37%) 46 (63%) 1 SLN positive (%) Macrometastases Micrometastases Isolated Tumoral Cells 2 (14,3%) 3 (21,4%) - 17 (23.3%) 7 (9.6%) 3 (4.1%) 0.48 Lymphadenectomy Yes Not 2 (14.3%) 12 (85.7%) 15 (19.5%) 62 (88.2%) 1 Lymphadenectomy outcomes LN removed, mean (SD) Number of positive LN 0 < 3 ≥ 3 20.5 (6.3) - 2 (100%) - 19.9 (4.6) 4 (26.7%) 8 (53.3%) 3 (20%) 0.33 0.89 ypN* ypN0 ypN1 ypN2 ypN3 ypNx 9 (64.3%) 5 (35.7%) - - - 49 (63.6%) 21 (27.3%) 2 (2.6%) 2 (2.6%) 3 (3.3%) 0.45 Abbreviations: LN, lymph nodes; n, number of patients; NET, neoadjuvant endocrine therapy; SD, standard deviations; SLN, sentinel lymph node. *ypN summarized the number of positive SLN and positive LN at lymphadenectomy Table 3 details the local and systemic adjuvant therapy and the results of pathological specimen evaluation. Interestingly, pathological complete response was observed in one patient with a cT2N0 luminal B-like tumor. Ki-67 staining after NET fell to < 10% in most patients (60.4%). The PEPI score was not evaluated until 2014, but since then 20 of 77 patients (26%) have had a PEPI score of ≥ 4; only four of these did not receive adjuvant chemotherapy due to low performance status or comorbidities. Table 3 Local and systemic adjuvant therapy and outcomes Mean (SD) Nº of patients (%) SURGICAL PROCEDURES Breast Surgery Lumpectomy BCS + Oncoplasty Mastectomy Mastectomy + Reconstruction 49 (53.8%) 17 (18.7%) 19 (20.9%) 6 (6.6%) Axillary Lymph Node Dissection Yes Not 17 (18.7%) 74 (81.3%) SPECIMEN PATHOLOGICAL EVALUATION ypT 0 1 2 3 1 (1.1%) 26 (28.6%) 44 (48.4%) 20 (22%) Tumor size (mm), mean (SD) 37 (25.6) Ki-67 after NET 30% No response 1 (1.1%) 63 (69,2%) 27 (29.7%) PEPI score 0 1–3 ≥ 4 Missing 24 (26.4%) 33 (36.3%) 20 (22%) 14 (15.4%) RADIOTHERAPY Breast Radiotherapy Not Breast Thoracic wall 11 (12.1%) 66 (72.5%) 14 (15.4%) Axillary Radiotherapy None Level III and Supraclavicular All levels 69 (75.8%) 8 (8.8%) 14 (15.4%) SYSTEMIC ADJUVANT THERAPY Chemotherapy Yes Not 18 (19.8%) 73 (80.2%) Endocrine therapy Tamoxifen Letrozole 1 (1.1%) 90 (98.9%) FOLLOW-UP OUTCOMES Recurrences Local ipsilateral (breast) Contralateral Breast Cancer Systemic 1 (1.1%) 1 (1.1%) 3 (3.4%) Death Cancer progression Other causes 4 (4.5%) 1 (1.1%) 3 (3.4%) Abbreviations: %, percentage of patients; BCS: breast conservative surgery; PEPI: postoperative endocrine prognostic index; SD, standard deviation . After a mean follow-up of 50 months (standard deviation, 38; range 9–174 months), five recurrences and four deaths were reported (Table 3 ). A locoregional recurrence occurred in one patient with pN1mi disease (pre-NET cohort), contralateral breast cancer in one patient with ypN1a disease (post-NET cohort), and distant recurrences in three patients with pN0/ypN0 disease (one in the pre-NET cohort and two in the post-NET cohort). Of the four patients who died, only one was due to breast cancer. The 5-year OS was 92.4% (95%CI 84.5–100%), the BCSS was 98.3% (95%CI 94.9–100%), and the DDFS was 94.8% (95%CI 87.4–100%) in the overall sample (Fig. 3 ). When comparing DDFS and OS no significant differences were found between positive and negative SLNB. (Fig. 4 ). Discussion In our sample of 91 cN0 breast tumors from 89 patients under neoadjuvant endocrine therapy, SLNB was positive in 35.7% of cases when performed pre-NET and in 37% of cases post-NET. The overlap of pre- and post-NET results indicates that endocrine therapy has no effect on subclinical SLN-positive disease. In contrast, previous studies by our team on SLNB before and after neoadjuvant chemotherapy observed that NAC reduces SLNB involvement 3-fold in cN0 patients (from 42% pre-NAC to 12% post-NAC), indicating that NAC provides a benefit in subclinical SLN-positive disease 7 . No other studies have evaluated SLNB in the setting of NET but, based on the overlap of our results before and after NET, it appears that the effect on lymph nodes differs substantially between chemotherapy and endocrine therapy. Seeking to answer this question, Friedman et al 14 evaluated axillary downstaging in HR+/Her2-cN + tumors after neoadjuvant systemic treatment comparing the two therapies, and observed pathological complete response after NAC in 19 out of 137 cases (13.9%) versus three out of 41 (7.3%) after NET. Therefore, lymph node disease in HR+/Her2- tumors appears to be resistant to any systemic treatment, with very poor responses regardless of whether the systemic treatment administered is chemotherapy or endocrine therapy. Lymph node disease in HR+/Her2- tumors is not usually very extensive. In our study, only three patients with SLN macrometastases (17.6%) had > 3 positive nodes in the final pathology study. Similarly, Kantor et al. observed the presence of ≤ 3 positive nodes in surgery in 90% of patients with cN0 after NET 15 . These results suggest that most patients with cN0 disease treated with NET have a low nodal disease burden, and therefore, might be spared the morbidity associated with ALND. Additionally, the prognostic significance of residual nodal disease after NST differed based on the use of NAC or NET 16 . In the National Cancer Database of Massachusetts, no significant differences in 5-year OS were observed when comparing patients with residual isolated tumor cells or micrometastasis with those who had no residual nodal disease after NET 17 . Our findings support these data, with DDFS and OS at five years unrelated to SLNB involvement and both exceeding 95%. Therefore, NET does not seem to carry the same prognostic significance as the residual nodal disease reported after NAC 2 . Despite the behavioral differences between breast cancer surrogate molecular subtypes and the impact of different types of neoadjuvant systemic therapy (NAC or NET), axillary management after NET is currently extrapolated from NAC, meaning that patients who are cN0 at diagnosis and SLNB-positive after NET will undergo ALND 2 . Emerging data suggest that the residual nodal disease burden for cN0 HR+/HER2- after NET should be similar to that for cT1–T2N0 after primary surgery, and that this may be an opportunity to extrapolate management strategies used in the upfront surgery setting. Both ACOSOG Z0011 18,19 and AMAROS studies 20 ,21 have shown that cN0 patients undergoing primary surgery with one or two positive SLNBs did not benefit from ALND in terms of DDFS and OS. Thus, it might be possible to consider de-escalating axillary management strategies after NET, subject to the results of further studies that are needed to standardize surgical management. Regarding adjuvant systemic therapy in HR+/HER2- disease, one of the most important questions is who will benefit from chemotherapy and endocrine therapy. Nitz et al. observed that patients with ypN0–1 disease (≤ 3 lymph nodes) and low Ki-67 after a short NET can safely receive adjuvant ET alone 22 . Another tool for deciding the need for adjuvant chemotherapy is the PEPI score, based on residual tumor size and Ki-67 after NET, but the value for lymph node involvement is the same regardless of the number of positive nodes 11 . Interestingly, the POETIC trial demonstrated that Ki-67 measured two weeks after preoperative NET was able to predict survival outcomes, providing a basis for simple and inexpensive testing that could personalize adjuvant treatment in HR+/ HER2- disease regardless of the axillary involvement 23 . Limitations of the study include the retrospective design and the small number of pre-NET SLNBs but it nevertheless provides an understanding of the low effect of NET on axillary tumor burden. Another limitation of our study is the relatively short follow-up (50 months) given that recurrences in HR+/HER2- disease may occur beyond 5 or 10 years from surgery. Despite these limitations, our study is one of the few to have exclusively analyzed the effect of NET on patients with cN0 disease at a single institution. Another important consideration is that most patients undergoing NET were over the age of 70, and in these patients, survival depended more on other associated comorbidities than on breast cancer diagnosis (e.g., only one out of four deaths was related to breast cancer). In fact, in 2006 a clinical trial showed that avoiding axillary clearance in clinically node-negative women aged ≥ 60 years receiving NET had the same prognosis with better early quality of life than ALND; therefore, even SLNB could have been avoided for this population with HR+/HER2- disease 8 . Nevertheless, since life expectancy has risen over the years, SLNB was performed in most of these patients, and if positive, ALND might be offered. In the context of these findings, Kantor et al. proposed a new tailored approach to axillary management after NET 16 based on performing an axillary ultrasound evaluation at the time of diagnosis to enumerate the suspicious lymph nodes. Then, for candidates for NET who had cN0 disease at diagnosis and ≤ 3 SLNB-positive nodes following NET, those authors recommend routinely omitting ALND. For patients who have biopsy-proven cN1 disease with ≤ 3 suspicious nodes by axillary ultrasound following NET, they recommend performing SLNB in addition to the clipped biopsy-proven node, only omitting ALND when 1–2 positive nodes are found. This approach may reduce axillary morbidity in a significant proportion of patients treated with NET, but to date there are no studies that have demonstrated its safety. Further prospective studies on the axillary management approach after NET are needed to establish consensus management of the axilla in patients with HR+/HER2- disease. Our group has designed a phase 3 randomized multicenter clinical trial (Axillary Lymph Node Dissection Versus Axillary Radiotherapy in Patients with Positive Sentinel Node after Neoadjuvant Therapy: ADARNAT, NCT04889924), to demonstrate whether ALND can be safely omitted in patients with ≤ 3 SLN macrometastases following NAC or NET in order to reduce the morbidity associated with ALND (recruitment is ongoing). Conclusions More than 30% of cN0 HR+/HER2- breast cancer patients treated with NET have a positive SLNB, irrespective of whether assessment is performed before or after neoadjuvant therapy. This suggests that the therapy has little effect on the axilla. In addition, survival may not be related to axillary involvement in these patients, who tend to present low residual axillary disease burden. Therefore, future efforts should focus on de-escalating ALND after NET. Declarations Funding: This research received no external funding. Acknowledgments: We thank Michael Maudsley for language revision. Author Contributions: Conceptualization and methodology: AGT, SF, and CF; Data curation: SF, IC, HC, RO; formal analyses: AGT, IC and HC; writing original draft preparation: AGT, CF, SP, ML.; writing, review, and editing, SF, MG, TS, EM, MJP, AG, MB, AB, RO, AP, JP, EF, MC, AL, SP. All authors have read and agreed to the published version of the manuscript Institutional Review Board Statement : The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of Hospital Universitari de Bellvitge (protocol code 247/06, approved in November 2006) Informed Consent Statement: Informed consent was obtained from all study participants. Data Availability Statement: Data were collected from computerized medical histories and the Catalan Public Health computerized network. The system was accessed with non-transferable passwords, ensuring patient confidentiality and privacy. The patient data were also anonymized for the analysis. All confidential patient data was protected according to national standards. Conflict of Interest: S.P. has served as an advisor/consultant for AstraZeneca, Daiichi Sankyo Eisai, Novartis, Polyphor, Roche, Pierre-Fabre, Pfizer and SeattleGenetics. All other authors declare that they have no conflicts of interest. References Sella T, Weiss A, Mittendorf EA, King TA, Pilewskie M, Giuliano AE, et al. Neoadjuvant Endocrine Therapy in Clinical Practice: A Review. JAMA Oncol. 2021;7(11):1700–8. Weiss A, King TA, Mittendorf EA. The Landmark Series: Neoadjuvant Endocrine Therapy for Breast Cancer. Ann Surg Oncol. 2020;27(9):3393–401. Kuehn T, Bauerfeind I, Fehm T, Fleige B, Hausschild M, Helms G, et al. 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Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA - J Am Med Assoc. 2017;318(10):918–26. Donker M, van Tienhoven G, Straver ME, Meijnen P, van de Velde CJH, Mansel RE, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): A randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15(12):1303–10. Bartels SAL, Donker M, Poncet C, Sauv N, Straver ME, Mansel RE, et al. Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer : 10-Year Results of the Randomized Controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol. 2022;1–8. Nitz UA, Gluz O, Kümmel S, Christgen M, Braun M, Aktas B, et al. Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2– Early Breast Cancer. J Clin Oncol. 2022; Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21(11):1443–54. Cite Share Download PDF Status: Published Journal Publication published 12 Apr, 2023 Read the published version in Breast Cancer Research and Treatment → Version 1 posted Editorial decision: Major Revisions Needed 02 Feb, 2023 Reviewers agreed at journal 16 Jan, 2023 Reviewers invited by journal 16 Jan, 2023 Editor invited by journal 29 Dec, 2022 Editor assigned by journal 21 Dec, 2022 First submitted to journal 20 Dec, 2022 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 Advisory Board 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-2394671","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":168226749,"identity":"bc6405e8-f56f-4157-bc77-ad2abe2e1a4b","order_by":0,"name":"Amparo Garcia-Tejedor","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABQUlEQVRIie3QMUvDQBQH8HcEdEm59YVK8xUuBEIHcfVrRApOAQUXoRALAV0irhEHB7+A4uJ4JdAsxa4HdmiXTh0iLgl08EWpQ9M4C95/uOTC++XdOwAdnT8bAcARmJwB0s6sPtHL7u8ErQRA+oC4JghG9fQbEQr1RWBNoJHwm4dFXpwehO5bJOXRZTe0D6+H8/KlG/IIWF4W9b+rhXsbix5605FPBNEZv/bc1hgRUzCseMvBlHQNEAZ6KhDSp0onCbw2Iwsp7IBZJ7bKPohcoJuc5N/kfulZJRGbCFvViZjEVZcUBQY0/jlVoulhi4ggYmzp4ijzjMUis5LpSFTEejQDt5rFekpZ1N47rpHOJHuGYtXn/C6az3IRcvtq7NCNhbyTRcP35X59fNzsLCQtbAA/ay1cbl7IoLlYR0dH53/mEyXragiqi3Q2AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-3398-0570","institution":"Hospital Universitario Bellvitge-IDIBELL","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Amparo","middleName":"","lastName":"Garcia-Tejedor","suffix":""},{"id":168226750,"identity":"ad731133-5d99-4044-9721-4657f0794eb9","order_by":1,"name":"Sergi 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SA","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hugo","middleName":"","lastName":"Calpelo","suffix":""},{"id":168226756,"identity":"6f4f3bdd-de07-401a-8e79-346229cb0f73","order_by":7,"name":"Raul Ortega","email":"","orcid":"","institution":"Bellvitge University Hospital: Hospital Universitari de Bellvitge","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Raul","middleName":"","lastName":"Ortega","suffix":""},{"id":168226757,"identity":"2053f9a7-fad5-43c9-938c-927593bbefb1","order_by":8,"name":"Anna Petit","email":"","orcid":"","institution":"Bellvitge University Hospital: Hospital Universitari de Bellvitge","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Petit","suffix":""},{"id":168226758,"identity":"0c057604-de6d-4b4e-8b06-2c62ea28935b","order_by":9,"name":"Anna Guma","email":"","orcid":"","institution":"Bellvitge University Hospital: Hospital Universitari de Bellvitge","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Guma","suffix":""},{"id":168226759,"identity":"942fcb2c-a41d-4fb9-adaf-6ad590a7f4fa","order_by":10,"name":"Miriam Campos","email":"","orcid":"","institution":"Bellvitge University Hospital: Hospital Universitari de Bellvitge","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Miriam","middleName":"","lastName":"Campos","suffix":""},{"id":168226760,"identity":"c2875dea-09f1-43ff-9918-046e412518b8","order_by":11,"name":"Agostina Stradella","email":"","orcid":"","institution":"Institut Català d’Oncologia: Institut Catala d'Oncologia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Agostina","middleName":"","lastName":"Stradella","suffix":""},{"id":168226761,"identity":"256a8b3d-5672-4063-8490-41b102bc36d5","order_by":12,"name":"Ana López-Ojeda","email":"","orcid":"","institution":"Bellvitge University Hospital: Hospital Universitari de Bellvitge","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"López-Ojeda","suffix":""}],"badges":[],"createdAt":"2022-12-19 18:13:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2394671/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2394671/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10549-023-06926-y","type":"published","date":"2023-04-12T20:27:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":31775360,"identity":"646e2f5c-a4f9-4ccc-b1dc-50fee4130c82","added_by":"auto","created_at":"2023-01-18 23:40:11","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":322210,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy flow chart\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations: \u003c/strong\u003eHER2: human epidermal growth factor receptor 2; NET: neoadjuvant endocrine therapy; SLNB:\u003cstrong\u003e \u003c/strong\u003esentinel lymph node biopsy.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2394671/v1/be5ca1c4f7c83144d8c4588c.jpg"},{"id":31774217,"identity":"84fd39e4-0126-45ee-830b-ee11892176d5","added_by":"auto","created_at":"2023-01-18 23:32:11","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":680700,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMammographic evaluation of a breast tumor before and after neoadjuvant endocrine therapy (NET), with partial response. (a,b) Craniocaudal (CC) and oblique projection of breast cancer tumor at diagnosis (c,d) CC and medio-lateral projection of breast cancer tumor with metallic marker (e,f) CC and oblique projection 6 months after NET.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2394671/v1/cc3cbb0824dfe2d8f56f8628.jpg"},{"id":31774215,"identity":"d2627773-1161-4d24-a97e-d4db03920c81","added_by":"auto","created_at":"2023-01-18 23:32:11","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":675759,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival curves\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2394671/v1/9f8df57f8b65ecbdda23bc62.jpg"},{"id":31775361,"identity":"f6f87da0-90a0-4910-bce9-66749158613d","added_by":"auto","created_at":"2023-01-18 23:40:11","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":701554,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival curves according to axillary involvement; (a) Distant disease-free survival (DDFS); (b) overall survival (OS)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2394671/v1/1ac468efb67ac2dfdb14cc44.jpg"},{"id":44724970,"identity":"87c303f5-de72-4632-94e7-d89685f03b6a","added_by":"auto","created_at":"2023-10-16 20:38:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":711676,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2394671/v1/ba75c900-3660-4f5c-8ef2-5be4ca9574c7.pdf"}],"financialInterests":"","formattedTitle":"Management of the axilla in postmenopausal patients with cN0 hormone receptor-positive/ HER2-negative breast cancer treated with neoadjuvant endocrine therapy and its prognostic impact.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors are the most common type of breast cancer, accounting for approximately 70% of cases. This subgroup of tumors has a better prognosis than others and is less sensitive to chemotherapy, and so requires different therapeutic approaches. In contrast, the axillary management of these patients does not differ from that applied in other more aggressive subtypes.\u003c/p\u003e \u003cp\u003eSeveral clinical trials have demonstrated that neoadjuvant endocrine therapy (NET) in postmenopausal patients can downsize HR+/HER2- tumors and facilitate breast-conserving surgery\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Aromatase inhibitors are the treatment of choice\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. However, axillary management strategies are underreported in these patients; indeed, they have been excluded not just from the large trials evaluating the feasibility of sentinel lymph node biopsy (SLNB) after preoperative therapy\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e but also from most of the ongoing clinical trials investigating regional nodal radiation after positive SLNB and neoadjuvant systemic therapy (NST). As a result, information on axillary management in the NET setting is lacking.\u003c/p\u003e \u003cp\u003eNeoadjuvant chemotherapy (NAC) has been shown to reduce the requirement for axillary lymph node dissection (ALND) in clinically node-positive (cN+) patients, since it achieves a complete pathological axillary response (pCR) in more than 60% of cases, especially for HER2-positive and triple negative tumors\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. By contrast, the incidence of axillary pCR after NET is much lower (\u0026lt;\u0026thinsp;10%)\u003csup\u003e6\u003c/sup\u003e. Moreover, in node-negative (cN0) disease, ALND rates also fell from 42% when performed before NAC to 12% following NAC\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, thanks to the downstaging of the undetectable lymph nodes involved. However, no data on SLNB before or after NET were reported.\u003c/p\u003e \u003cp\u003eThe lack of significant differences in survival outcomes observed in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;60 years with HR+/HER2- disease treated with or without ALND\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e suggests an opportunity to de-escalate treatment when patients have limited residual nodal disease. In fact, information from the National Cancer Database after examining patterns of axillary management in patients with cN0 HR+/HER2- disease revealed that those who had a positive SLNB after NET were less likely to complete ALND, thus favoring the adoption of less aggressive management strategies by this group\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Nevertheless, the long-term impact of omitting ALND in this setting remains unknown.\u003c/p\u003e \u003cp\u003eThe efficacy and tolerability of NET have been widely reported, especially in elderly patients, and its superior cost-efficacy balance compared with NAC has been stressed. However, it is not widely used in clinical practice\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Given the limited data available for axillary management after NET, the present study aimed to evaluate the differences in performing the SLNB before or after NET in patients with cN0 HR+/HER2- breast cancer, as well as its impact on adjuvant chemotherapy decision-making and prognosis.\u003c/p\u003e"},{"header":"Material And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study of a prospectively maintained database included cN0 breast cancer patients treated with NET at Institut Catal\u0026agrave; d\u0026rsquo;Oncologia-Hospital Universitari Bellvitge, between December 2006 and March 2022. In that period, 522 patients were identified as candidates for NST, and 91 were finally treated with NET (17.4%) (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The Hospital Universitari Bellvitge Institutional Review Board approved the study (247/06), and all patients signed informed consent forms. The anonymization of all patient data was ensured, and their confidential information protected in accordance with the national regulations.\u003c/p\u003e \u003cp\u003ePatients were required to meet all the following eligibility criteria: (1) postmenopausal women, or men; (2) palpable breast tumor; (3) clinical and radiological cN0 at diagnosis (by axillary ultrasound); (4) invasive breast carcinoma in tumor core biopsy, estrogen receptor (ER)\u0026thinsp;\u0026gt;\u0026thinsp;50% and HER2-negative tumors; (5) NET; and (6) willingness to undergo surgery following NET. We excluded patients who had ALN-positive disease at diagnosis by fine-needle aspiration, NAC, and HER2-positive tumors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatments and cohorts\u003c/h2\u003e \u003cp\u003e NET was indicated in patients with HR+/HER2- palpable breast tumor according to our multidisciplinary committee. Treatment consisted of 2.5 mg letrozole in women and 20 mg tamoxifen in men for 6\u0026ndash;12 months, depending on response. Conservative or radical breast surgery following NET was decided according to tumor response, tumor size, and predictable aesthetic results.\u003c/p\u003e \u003cp\u003eCases were distributed into two cohorts based on when they underwent SLNB before (pre-NET) and after NET (post-NET). SLNB was performed before NST from December 2006 to April 2014 and following NST thereafter according to our breast cancer guidelines. Peritumor injection of 3 mCi/mL 99m-technetium radiocolloid (99m-Tc) was administered for lymphatic mapping 24 hours before the SLNB. When initial migration had not been observed on a previous gammagraphic map, we performed a second injection with 99m-Tc the day before to improve migration. Radioactivity was detected with an intraoperative gamma probe (Europrobe; Britec, Sheffield, United Kingdom).\u003c/p\u003e \u003cp\u003eIn the pathology department, the SLN and adipose tissue were fixed in 10% formaldehyde and completely embedded in paraffin, and processed in 3-mm sections, separated by 150 mm, three stained using hematoxylin and eosin and three stained using AE1/AE3 cytokeratin. Micrometastasis was defined as a small cluster of cells measuring 0.2\u0026ndash;2 mm, and macrometastasis as \u0026gt;\u0026thinsp;2 mm. In both cohorts, deferred ALND was performed in patients with SLNB macrometastasis, except in selected elderly women in whom it was omitted in accordance with the Rudenstam et al. guidelines\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Patients with negative SLNs or with SLN micrometastasis did not undergo further treatment of the axilla.\u003c/p\u003e \u003cp\u003eAdjuvant chemotherapy was offered to patients with a postoperative endocrine prognostic index\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e (PEPI score)\u0026thinsp;\u0026gt;\u0026thinsp;3 if they were aged\u0026thinsp;\u0026lt;\u0026thinsp;80 years and had a good performance status (\u0026lt;\u0026thinsp;2). Most of the schemas included taxanes; however, therapy was adapted to each patient depending on their associated comorbidities prior to oncogeriatric screening. All patients received the same adjuvant endocrine therapy as in the neoadjuvant setting (2.5 mg letrozole, except in cases of progression during NET) to complete a minimum of five years. All patients had radiotherapy of the breast or chest wall according to our institutional guidelines after breast-conserving surgery and in cases with cT3-T4 tumors after mastectomy. Patients with SLNB-positive disease also received supraclavicular radiotherapy, including level III-ALN.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eVariables\u003c/h2\u003e \u003cp\u003eWe recorded the following clinical and pathologic variables: age, tumor size before and after NET, histological type, Nottingham histological grade, lymphovascular invasion, hormonal receptors status, proliferative index by Ki-67 staining, percentage of TILs (considered negative if\u0026thinsp;\u0026lt;\u0026thinsp;5% of stromal TILs), treatment duration, type of breast and axillary surgery, SLN identification rate, SLN involvement, ALND rate, and any adjuvant treatments. Samples were divided into two surrogate subtypes according to PR and Ki-67 expression\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e: Luminal A-like, for progesterone receptor (PR)\u0026thinsp;\u0026gt;\u0026thinsp;20%, and Ki-67\u0026thinsp;\u0026lt;\u0026thinsp;20%; and Luminal B-like (HER2-), for PR\u0026thinsp;\u0026lt;\u0026thinsp;20% or Ki-67\u0026thinsp;\u0026gt;\u0026thinsp;20%. The Ki-67 proliferative index was grouped as \u0026gt;\u0026thinsp;30% or \u0026lt;\u0026thinsp;30% based on the results from a receiver operating characteristic curve (data not shown) at diagnosis and \u0026gt;\u0026thinsp;10% or \u0026lt;\u0026thinsp;10% after NET. Evaluation of clinical and radiological responses was grouped according to World Health Organization criteria, as complete response, partial response, no response, or progression\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Pathological complete response was considered when the pathologist observed 100% fibrosis replacing the invasive carcinoma and no axillary involvement, partial response if\u0026thinsp;\u0026gt;\u0026thinsp;30% of fibrosis, and no response if\u0026thinsp;\u0026lt;\u0026thinsp;30% fibrosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up\u003c/h2\u003e \u003cp\u003eThe patients were evaluated clinically and radiologically every three months before surgery. Radiological assessment included mammography and ultrasound of the breast and axilla in all cases, with magnetic resonance imaging reserved for selected cases. After surgery, patients were followed clinically every six months, with an annual mammography. Recurrences were defined as local when present in the ipsilateral breast or lymph nodes and systemic when they involved contralateral lymph nodes or other organs. Contralateral tumors were recorded separately.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables are presented as the number of cases and proportions, whereas normally distributed continuous variables are presented as means and standard deviations (SD). Differences between the pre-NET and post-NET groups were analyzed by the chi-square test or Fisher\u0026rsquo;s exact test for categorical variables and by the Student t-test for continuous variables. The level of statistical significance was arbitrarily set at 5%. Statistical analyses were performed using IBM SPSS version 23.0 (IBM Corp., Armonk, NY, USA). Distant disease-free survival (DDFS) was defined as the time from diagnosis to distant recurrence, a second primary invasive cancer, or death from any cause. Breast cancer specific survival (BCSS) was calculated from diagnosis until death from breast cancer, and overall survival (OS) was calculated from diagnosis until death from any cause. OS, BCSS, and DDFS were calculated at 5 years with their 95% confidence intervals (95%CIs). Kaplan\u0026ndash;Meier survival curves of DDFS and OS were obtained in relation to the status of the axilla, which was grouped as ypN0 or ypN+, to assess the impact of affected lymph nodes in the context of HR\u0026thinsp;+\u0026thinsp;HER2- tumors, and the differences were computed by the log-rank test. Patients without events were censored at the time of the last follow-up.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFrom December 2006 to March 2022, we included 89 patients who underwent NET and SLNB (88 women and 1 man); two of the patients had bilateral synchronous disease, so the final sample comprised 91 cases. SLNB was performed before NET in 14 cases (pre-NET cohort) and following NET in 77 (post-NET cohort). Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the baseline characteristics of the patients and tumors, as well as the clinical-radiological response in the overall sample. The seven cT1N0 cases included were due to bilateral tumors (n\u0026thinsp;=\u0026thinsp;1), comorbidity associated with the diagnosis (n\u0026thinsp;=\u0026thinsp;4), or COVID infection requiring surgical delay (n\u0026thinsp;=\u0026thinsp;2). Mammographic evaluation of a breast tumor before and after NET, with partial response, is shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab1\" style=\"text-align: inherit;\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient and tumor characteristics*\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u0026ordm; of patients (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e69.5 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecT\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (7.7%)\u003c/p\u003e\n \u003cp\u003e57 (62.6%)\u003c/p\u003e\n \u003cp\u003e20 (22%)\u003c/p\u003e\n \u003cp\u003e7 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor size, mm**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39.8 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003cp\u003eNo special type (Ductal)\u003c/p\u003e\n \u003cp\u003eLobular\u003c/p\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64 (70.3%)\u003c/p\u003e\n \u003cp\u003e25 (27.5%)\u003c/p\u003e\n \u003cp\u003e2 (2.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNottingham histological grade\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003eNot evaluable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (28.6%)\u003c/p\u003e\n \u003cp\u003e58 (63.7%)\u003c/p\u003e\n \u003cp\u003e6 (6.6%)\u003c/p\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKi-67\u003c/p\u003e\n \u003cp\u003e\u0026le; 30%\u003c/p\u003e\n \u003cp\u003e\u0026gt; 30%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80 (87.9%)\u003c/p\u003e\n \u003cp\u003e11 (12.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMolecular surrogate subtype\u003c/p\u003e\n \u003cp\u003eLuminal A-like\u003c/p\u003e\n \u003cp\u003eLuminal B-like\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39 (42.9%)\u003c/p\u003e\n \u003cp\u003e52 (57.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVascular invasion\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e70 (76.9%)\u003c/p\u003e\n \u003cp\u003e21 (23.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTILs\u003c/p\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (17,6%)\u003c/p\u003e\n \u003cp\u003e52 (57.1%)\u003c/p\u003e\n \u003cp\u003e23 (25.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical-radiological response\u003c/p\u003e\n \u003cp\u003eComplete\u003c/p\u003e\n \u003cp\u003ePartial\u0026thinsp;\u0026gt;\u0026thinsp;50%\u003c/p\u003e\n \u003cp\u003eNo response\u003c/p\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (6.6%)\u003c/p\u003e\n \u003cp\u003e73 (80.2%)\u003c/p\u003e\n \u003cp\u003e11 (12.1%)\u003c/p\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eAbbreviations: SD, standard deviation; %, percentage of patients; TILs, tumor-infiltrating lymphocytes\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e* Data related to 91 tumours in 89 patients.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e**Tumor size measured by magnetic resonance imaging in 58 cases and ultrasounds in 33.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eSLNB identification rate was higher before NET: 100% versus 94.5% after NET (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). In three of the four undetectable cases, ALND was omitted because the patients were elderly. SLNB positivity was similar whether performed before or after NET (35.7% versus 37% respectively) and the rate of omission of ALND was similar in the two cohorts (85.7% pre-NET and 88.2% post-NET). Note that only three of the 17 ALND performed (17.6%) had\u0026thinsp;\u0026gt;\u0026thinsp;3 positive nodes in the final pathology report, and that all these cases had more than one positive SLNB.\u003c/p\u003e\n\u003cp\u003eTable 2. Outcomes of axillary surgery\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"567\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.80599647266314%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003ePre-NET\u003c/p\u003e\n \u003cp\u003e(n = 14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003ePost-NET\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n=77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.63668430335097%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.80599647266314%\"\u003e\n \u003cp\u003eSLN Identification Rate (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e14 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e73 (94.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.63668430335097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.80599647266314%\"\u003e\n \u003cp\u003eSLN removed, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e1.7 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e1.8 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.63668430335097%\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.80599647266314%\"\u003e\n \u003cp\u003eSLN pathological result\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Positive\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (35.7%)\u003c/p\u003e\n \u003cp\u003e9 (64,3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27 (37%)\u003c/p\u003e\n \u003cp\u003e46 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.63668430335097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.80599647266314%\"\u003e\n \u003cp\u003eSLN positive (%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Macrometastases\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Micrometastases\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Isolated Tumoral Cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (14,3%)\u003c/p\u003e\n \u003cp\u003e3 (21,4%)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (23.3%)\u003c/p\u003e\n \u003cp\u003e7 (9.6%)\u003c/p\u003e\n \u003cp\u003e3 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.63668430335097%\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.80599647266314%\"\u003e\n \u003cp\u003eLymphadenectomy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Not\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (14.3%)\u003c/p\u003e\n \u003cp\u003e12 (85.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15 (19.5%)\u003c/p\u003e\n \u003cp\u003e62 (88.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.63668430335097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.80599647266314%\"\u003e\n \u003cp\u003eLymphadenectomy outcomes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; LN removed, mean (SD)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Number of positive LN\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026lt; 3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026ge;\u0026nbsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20.5 (6.3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e2 (100%)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e19.9 (4.6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (26.7%)\u003c/p\u003e\n \u003cp\u003e8 (53.3%)\u003c/p\u003e\n \u003cp\u003e3 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.63668430335097%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"29.80599647266314%\"\u003e\n \u003cp\u003eypN*\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; ypN0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; ypN1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; ypN2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; ypN3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; ypNx\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (64.3%)\u003c/p\u003e\n \u003cp\u003e5 (35.7%)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.278659611992946%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e49 (63.6%)\u003c/p\u003e\n \u003cp\u003e21 (27.3%)\u003c/p\u003e\n \u003cp\u003e2 (2.6%)\u003c/p\u003e\n \u003cp\u003e2 (2.6%)\u003c/p\u003e\n \u003cp\u003e3 (3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.63668430335097%\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: LN, lymph nodes; n, number of patients;\u0026nbsp;NET, neoadjuvant endocrine therapy; SD, standard deviations; SLN, sentinel lymph node.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e*ypN summarized the number of positive SLN and positive LN at lymphadenectomy\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e details the local and systemic adjuvant therapy and the results of pathological specimen evaluation. Interestingly, pathological complete response was observed in one patient with a cT2N0 luminal B-like tumor. Ki-67 staining after NET fell to \u0026lt;\u0026thinsp;10% in most patients (60.4%). The PEPI score was not evaluated until 2014, but since then 20 of 77 patients (26%) have had a PEPI score of \u0026ge;\u0026thinsp;4; only four of these did not receive adjuvant chemotherapy due to low performance status or comorbidities.\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab3\" style=\"text-align: inherit;\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eLocal and systemic adjuvant therapy and outcomes\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u0026ordm; of patients (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eSURGICAL PROCEDURES\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBreast Surgery\u003c/p\u003e\n \u003cp\u003eLumpectomy\u003c/p\u003e\n \u003cp\u003eBCS\u0026thinsp;+\u0026thinsp;Oncoplasty\u003c/p\u003e\n \u003cp\u003eMastectomy\u003c/p\u003e\n \u003cp\u003eMastectomy\u0026thinsp;+\u0026thinsp;Reconstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49 (53.8%)\u003c/p\u003e\n \u003cp\u003e17 (18.7%)\u003c/p\u003e\n \u003cp\u003e19 (20.9%)\u003c/p\u003e\n \u003cp\u003e6 (6.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAxillary Lymph Node Dissection\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNot\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (18.7%)\u003c/p\u003e\n \u003cp\u003e74 (81.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eSPECIMEN PATHOLOGICAL EVALUATION\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eypT\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003cp\u003e26 (28.6%)\u003c/p\u003e\n \u003cp\u003e44 (48.4%)\u003c/p\u003e\n \u003cp\u003e20 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor size (mm), mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKi-67 after NET\u003c/p\u003e\n \u003cp\u003e\u0026lt; 10\u003c/p\u003e\n \u003cp\u003e\u0026ge; 10\u003c/p\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (60.4%)\u003c/p\u003e\n \u003cp\u003e21 (23.1%)\u003c/p\u003e\n \u003cp\u003e15 (16.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePathological response\u003c/p\u003e\n \u003cp\u003eComplete\u003c/p\u003e\n \u003cp\u003ePartial\u0026thinsp;\u0026gt;\u0026thinsp;30%\u003c/p\u003e\n \u003cp\u003eNo response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003cp\u003e63 (69,2%)\u003c/p\u003e\n \u003cp\u003e27 (29.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePEPI score\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;3\u003c/p\u003e\n \u003cp\u003e\u0026ge; 4\u003c/p\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (26.4%)\u003c/p\u003e\n \u003cp\u003e33 (36.3%)\u003c/p\u003e\n \u003cp\u003e20 (22%)\u003c/p\u003e\n \u003cp\u003e14 (15.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eRADIOTHERAPY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBreast Radiotherapy\u003c/p\u003e\n \u003cp\u003eNot\u003c/p\u003e\n \u003cp\u003eBreast\u003c/p\u003e\n \u003cp\u003eThoracic wall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (12.1%)\u003c/p\u003e\n \u003cp\u003e66 (72.5%)\u003c/p\u003e\n \u003cp\u003e14 (15.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAxillary Radiotherapy\u003c/p\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003cp\u003eLevel III and Supraclavicular\u003c/p\u003e\n \u003cp\u003eAll levels\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69 (75.8%)\u003c/p\u003e\n \u003cp\u003e8 (8.8%)\u003c/p\u003e\n \u003cp\u003e14 (15.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eSYSTEMIC ADJUVANT THERAPY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNot\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (19.8%)\u003c/p\u003e\n \u003cp\u003e73 (80.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndocrine therapy\u003c/p\u003e\n \u003cp\u003eTamoxifen\u003c/p\u003e\n \u003cp\u003eLetrozole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003cp\u003e90 (98.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eFOLLOW-UP OUTCOMES\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRecurrences\u003c/p\u003e\n \u003cp\u003eLocal ipsilateral (breast)\u003c/p\u003e\n \u003cp\u003eContralateral Breast Cancer\u003c/p\u003e\n \u003cp\u003eSystemic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003cp\u003e3 (3.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003cp\u003eCancer progression\u003c/p\u003e\n \u003cp\u003eOther causes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4.5%)\u003c/p\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003cp\u003e3 (3.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eAbbreviations: %, percentage of patients; BCS: breast conservative surgery; PEPI: postoperative endocrine prognostic index; SD, standard deviation .\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eAfter a mean follow-up of 50 months (standard deviation, 38; range 9\u0026ndash;174 months), five recurrences and four deaths were reported (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). A locoregional recurrence occurred in one patient with pN1mi disease (pre-NET cohort), contralateral breast cancer in one patient with ypN1a disease (post-NET cohort), and distant recurrences in three patients with pN0/ypN0 disease (one in the pre-NET cohort and two in the post-NET cohort). Of the four patients who died, only one was due to breast cancer. The 5-year OS was 92.4% (95%CI 84.5\u0026ndash;100%), the BCSS was 98.3% (95%CI 94.9\u0026ndash;100%), and the DDFS was 94.8% (95%CI 87.4\u0026ndash;100%) in the overall sample (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). When comparing DDFS and OS no significant differences were found between positive and negative SLNB. (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our sample of 91 cN0 breast tumors from 89 patients under neoadjuvant endocrine therapy, SLNB was positive in 35.7% of cases when performed pre-NET and in 37% of cases post-NET. The overlap of pre- and post-NET results indicates that endocrine therapy has no effect on subclinical SLN-positive disease. In contrast, previous studies by our team on SLNB before and after neoadjuvant chemotherapy observed that NAC reduces SLNB involvement 3-fold in cN0 patients (from 42% pre-NAC to 12% post-NAC), indicating that NAC provides a benefit in subclinical SLN-positive disease\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. No other studies have evaluated SLNB in the setting of NET but, based on the overlap of our results before and after NET, it appears that the effect on lymph nodes differs substantially between chemotherapy and endocrine therapy. Seeking to answer this question, Friedman et al\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e evaluated axillary downstaging in HR+/Her2-cN\u0026thinsp;+\u0026thinsp;tumors after neoadjuvant systemic treatment comparing the two therapies, and observed pathological complete response after NAC in 19 out of 137 cases (13.9%) versus three out of 41 (7.3%) after NET. Therefore, lymph node disease in HR+/Her2- tumors appears to be resistant to any systemic treatment, with very poor responses regardless of whether the systemic treatment administered is chemotherapy or endocrine therapy.\u003c/p\u003e \u003cp\u003eLymph node disease in HR+/Her2- tumors is not usually very extensive. In our study, only three patients with SLN macrometastases (17.6%) had\u0026thinsp;\u0026gt;\u0026thinsp;3 positive nodes in the final pathology study. Similarly, Kantor et al. observed the presence of \u0026le;\u0026thinsp;3 positive nodes in surgery in 90% of patients with cN0 after NET\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. These results suggest that most patients with cN0 disease treated with NET have a low nodal disease burden, and therefore, might be spared the morbidity associated with ALND. Additionally, the prognostic significance of residual nodal disease after NST differed based on the use of NAC or NET\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In the National Cancer Database of Massachusetts, no significant differences in 5-year OS were observed when comparing patients with residual isolated tumor cells or micrometastasis with those who had no residual nodal disease after NET\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Our findings support these data, with DDFS and OS at five years unrelated to SLNB involvement and both exceeding 95%. Therefore, NET does not seem to carry the same prognostic significance as the residual nodal disease reported after NAC\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite the behavioral differences between breast cancer surrogate molecular subtypes and the impact of different types of neoadjuvant systemic therapy (NAC or NET), axillary management after NET is currently extrapolated from NAC, meaning that patients who are cN0 at diagnosis and SLNB-positive after NET will undergo ALND\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Emerging data suggest that the residual nodal disease burden for cN0 HR+/HER2- after NET should be similar to that for cT1\u0026ndash;T2N0 after primary surgery, and that this may be an opportunity to extrapolate management strategies used in the upfront surgery setting. Both ACOSOG Z0011\u003csup\u003e18,19\u003c/sup\u003e and AMAROS studies\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,21\u003c/sup\u003ehave shown that cN0 patients undergoing primary surgery with one or two positive SLNBs did not benefit from ALND in terms of DDFS and OS. Thus, it might be possible to consider de-escalating axillary management strategies after NET, subject to the results of further studies that are needed to standardize surgical management.\u003c/p\u003e \u003cp\u003eRegarding adjuvant systemic therapy in HR+/HER2- disease, one of the most important questions is who will benefit from chemotherapy and endocrine therapy. Nitz et al. observed that patients with ypN0\u0026ndash;1 disease (\u0026le;\u0026thinsp;3 lymph nodes) and low Ki-67 after a short NET can safely receive adjuvant ET alone\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Another tool for deciding the need for adjuvant chemotherapy is the PEPI score, based on residual tumor size and Ki-67 after NET, but the value for lymph node involvement is the same regardless of the number of positive nodes\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Interestingly, the POETIC trial demonstrated that Ki-67 measured two weeks after preoperative NET was able to predict survival outcomes, providing a basis for simple and inexpensive testing that could personalize adjuvant treatment in HR+/ HER2- disease regardless of the axillary involvement\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLimitations of the study include the retrospective design and the small number of pre-NET SLNBs but it nevertheless provides an understanding of the low effect of NET on axillary tumor burden. Another limitation of our study is the relatively short follow-up (50 months) given that recurrences in HR+/HER2- disease may occur beyond 5 or 10 years from surgery. Despite these limitations, our study is one of the few to have exclusively analyzed the effect of NET on patients with cN0 disease at a single institution.\u003c/p\u003e \u003cp\u003eAnother important consideration is that most patients undergoing NET were over the age of 70, and in these patients, survival depended more on other associated comorbidities than on breast cancer diagnosis (e.g., only one out of four deaths was related to breast cancer). In fact, in 2006 a clinical trial showed that avoiding axillary clearance in clinically node-negative women aged\u0026thinsp;\u0026ge;\u0026thinsp;60 years receiving NET had the same prognosis with better early quality of life than ALND; therefore, even SLNB could have been avoided for this population with HR+/HER2- disease\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Nevertheless, since life expectancy has risen over the years, SLNB was performed in most of these patients, and if positive, ALND might be offered. In the context of these findings, Kantor et al. proposed a new tailored approach to axillary management after NET\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e based on performing an axillary ultrasound evaluation at the time of diagnosis to enumerate the suspicious lymph nodes. Then, for candidates for NET who had cN0 disease at diagnosis and \u0026le;\u0026thinsp;3 SLNB-positive nodes following NET, those authors recommend routinely omitting ALND. For patients who have biopsy-proven cN1 disease with \u0026le;\u0026thinsp;3 suspicious nodes by axillary ultrasound following NET, they recommend performing SLNB in addition to the clipped biopsy-proven node, only omitting ALND when 1\u0026ndash;2 positive nodes are found. This approach may reduce axillary morbidity in a significant proportion of patients treated with NET, but to date there are no studies that have demonstrated its safety.\u003c/p\u003e \u003cp\u003eFurther prospective studies on the axillary management approach after NET are needed to establish consensus management of the axilla in patients with HR+/HER2- disease. Our group has designed a phase 3 randomized multicenter clinical trial (Axillary Lymph Node Dissection Versus Axillary Radiotherapy in Patients with Positive Sentinel Node after Neoadjuvant Therapy: ADARNAT, NCT04889924), to demonstrate whether ALND can be safely omitted in patients with \u0026le;\u0026thinsp;3 SLN macrometastases following NAC or NET in order to reduce the morbidity associated with ALND (recruitment is ongoing).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eMore than 30% of cN0 HR+/HER2- breast cancer patients treated with NET have a positive SLNB, irrespective of whether assessment is performed before or after neoadjuvant therapy. This suggests that the therapy has little effect on the axilla. In addition, survival may not be related to axillary involvement in these patients, who tend to present low residual axillary disease burden. Therefore, future efforts should focus on de-escalating ALND after NET.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments: \u003c/strong\u003eWe thank Michael Maudsley for language revision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eConceptualization and methodology: AGT, SF, and CF; Data curation: SF, IC, HC, RO; formal analyses: AGT, IC and HC; writing original draft preparation: AGT, CF, SP, ML.; writing, review, and editing, SF, MG, TS, EM, MJP, AG, MB, AB, RO, AP, JP, EF, MC, AL, SP. All authors have read and agreed to the published version of the manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement\u003c/strong\u003e:\u0026nbsp;The study\u0026nbsp;was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of\u0026nbsp;Hospital Universitari de Bellvitge\u0026nbsp;(protocol code\u0026nbsp;247/06,\u0026nbsp;approved in November 2006)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u003c/strong\u003e Informed consent was obtained from all study participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eData were collected from computerized medical histories and the Catalan Public Health computerized network. The system was accessed with non-transferable passwords, ensuring patient confidentiality and privacy.\u0026nbsp;The patient data were also anonymized for the analysis. All confidential patient data was protected according to national standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eS.P. has served as an advisor/consultant for AstraZeneca, Daiichi Sankyo Eisai, Novartis, Polyphor, Roche, Pierre-Fabre, Pfizer and SeattleGenetics. All other authors declare that they have no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSella T, Weiss A, Mittendorf EA, King TA, Pilewskie M, Giuliano AE, et al. Neoadjuvant Endocrine Therapy in Clinical Practice: A Review. JAMA Oncol. 2021;7(11):1700–8. \u003c/li\u003e\n\u003cli\u003eWeiss A, King TA, Mittendorf EA. The Landmark Series: Neoadjuvant Endocrine Therapy for Breast Cancer. Ann Surg Oncol. 2020;27(9):3393–401. \u003c/li\u003e\n\u003cli\u003eKuehn T, Bauerfeind I, Fehm T, Fleige B, Hausschild M, Helms G, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol. 2013 Jun;14(7):609–18. \u003c/li\u003e\n\u003cli\u003eSchmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810–21. \u003c/li\u003e\n\u003cli\u003eFernandez-Gonzalez S, Falo C, Pla MJ, Verdaguer P, Nuñez D, Guma A, et al. Predictive factors for omitting lymphadenectomy in patients with node-positive breast cancer treated with neo-adjuvant systemic therapy. Breast J. 2020;26(5):888–96. \u003c/li\u003e\n\u003cli\u003eStafford A, Williams A, Edmiston K, Cocilovo C, Cohen R, Bruce S, et al. Axillary Response in Patients Undergoing Neoadjuvant Endocrine Treatment for Node-Positive Breast Cancer: Systematic Literature Review and NCDB Analysis. Ann Surg Oncol. 2020;27(12):4669–77. \u003c/li\u003e\n\u003cli\u003eFernandez-Gonzalez S, Falo C, Pla MJ, Pernas S, Bajen M, Soler T, et al. The Shift From Sentinel Lymph Node Biopsy Performed Either Before or After Neoadjuvant Systemic Therapy in the Clinical Negative Nodes of Breast Cancer Patients. Results, and the Advantages and Disadvantages of Both Procedures. Clin Breast Cancer. 2017;1–7. \u003c/li\u003e\n\u003cli\u003eRudenstam CM, Zahrieh D, Forbes JF, Crivellari D, Holmberg SB, Rey P, et al. Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: First results of International Breast Cancer Study Group trial 10-93. J Clin Oncol. 2006;24(3):337–44. \u003c/li\u003e\n\u003cli\u003eWeiss A, Wong S, Golshan M, Freedman RA, Metzger O, Bellon J, et al. Patterns of Axillary Management in Stages 2 and 3 Hormone Receptor-Positive Breast Cancer by Initial Treatment Approach. Ann Surg Oncol. 2019;26(13):4326–36. \u003c/li\u003e\n\u003cli\u003eBarchiesi G, Mazzotta M, Krasniqi E, Pizzuti L, Marinelli D, Capomolla E, et al. Neoadjuvant endocrine therapy in breast cancer: Current knowledge and future perspectives. Int J Mol Sci. 2020;21(10):1–23. \u003c/li\u003e\n\u003cli\u003eChia YH, Ellis MJ, Ma CX. Neoadjuvant endocrine therapy in primary breast cancer: Indications and use as a research tool. Br J Cancer. 2010;103(6):759–64. \u003c/li\u003e\n\u003cli\u003eGoldhirsch a, Winer EP, Coates a S, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013 Sep;24(9):2206–23. \u003c/li\u003e\n\u003cli\u003eTirkes T, Hollar MA, Tann M, Kohli MD, Akisik F, Sandrasegaran K. Response criteria in oncologic imaging: Review of traditional and new criteria. Radiographics. 2013;33(5):1323–41. \u003c/li\u003e\n\u003cli\u003eFriedman-Eldar O, Ozmen T, El Haddi SJ, Goel N, Tjendra Y, Kesmodel SB, et al. Axillary Response to Neoadjuvant Therapy in Node-Positive, Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Patients: Predictors and Oncologic Outcomes. Ann Surg Oncol. 2022;(February). \u003c/li\u003e\n\u003cli\u003eKantor O, Wakeman M, Weiss A, Wong S, Laws A, Grossmith S, et al. Axillary Management After Neoadjuvant Endocrine Therapy for Hormone Receptor-Positive Breast Cancer. Ann Surg Oncol. 2021;28(3):1358–67. \u003c/li\u003e\n\u003cli\u003eKantor O, King TA. ASO Author Reflections: Tailoring Axillary Surgery After Neoadjuvant Endocrine Therapy for Breast Cancer. Ann Surg Oncol. 2021;28(3):1368–9. \u003c/li\u003e\n\u003cli\u003eKantor O, Wong S, Weiss A, Metzger O, Mittendorf EA, King TA. Prognostic significance of residual nodal disease after neoadjuvant endocrine therapy for hormone receptor-positive breast cancer. npj Breast Cancer. 2020;6(1):5–10. \u003c/li\u003e\n\u003cli\u003eGiuliano AE, Hunt KK, Ballman K V., Beitsch PD, Whitworth PW, Blumencranz PW, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA - J Am Med Assoc. 2011;305(6):569–75. \u003c/li\u003e\n\u003cli\u003eGiuliano AE, Ballman K V., McCall L, Beitsch PD, Brennan MB, Kelemen PR, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA - J Am Med Assoc. 2017;318(10):918–26. \u003c/li\u003e\n\u003cli\u003eDonker M, van Tienhoven G, Straver ME, Meijnen P, van de Velde CJH, Mansel RE, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): A randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15(12):1303–10. \u003c/li\u003e\n\u003cli\u003eBartels SAL, Donker M, Poncet C, Sauv N, Straver ME, Mansel RE, et al. Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer : 10-Year Results of the Randomized Controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol. 2022;1–8. \u003c/li\u003e\n\u003cli\u003eNitz UA, Gluz O, Kümmel S, Christgen M, Braun M, Aktas B, et al. Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2– Early Breast Cancer. J Clin Oncol. 2022; \u003c/li\u003e\n\u003cli\u003eSmith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21(11):1443–54. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Neoadjuvant endocrine therapy, sentinel lymph node biopsy, hormone-receptor-positive breast cancer, axillary management, axillary node dissection, de-escalation","lastPublishedDoi":"10.21203/rs.3.rs-2394671/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2394671/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo evaluate the differences when performing the sentinel lymph node biopsy (SLNB) before or after neoadjuvant endocrine therapy (NET) in breast cancer patients, and the impact of its timing on prognosis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective cohort study including 91 postmenopausal cases with clinically node-negative and hormone receptor-positive/HER2 negative (HR+/HER2-) breast cancer, treated with NET and SLNB at our institution. SLNB was performed pre-NET until 2014, and post-NET thereafter. Axillary lymph node dissection (ALND) was indicated only in SLNB-macrometastasis, although in selected elderly patients it was omitted. Kaplan-Meier survival curves were obtained in relation to the status of the axilla, and the differences assessed using the log-rank test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBetween December 2006 and March 2022, SLNB was performed pre-NET in 14 cases and post-NET in 77. SLNB-positivity was similar regardless of whether SLNB was performed before or after NET (35.7% and 37%, respectively), with 2/14 SLN macrometastases in the pre-NET cohort and 17/77 in the post-NET cohort. Only three patients (18.7%) with SLN macrometastasis had\u0026thinsp;\u0026gt;\u0026thinsp;3 positive nodes following axillary node dissection. The 5-year overall survival and distant disease-free survival were 92.4% and 94.8% respectively, with no significant differences according to SLNB status.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSLN positivity did not differ according to its timing (before or after NET). Therefore, NET has no effect on lymph node clearance. Furthermore, the prognosis is good regardless of the axillary involvement. Therefore, factors other than axillary involvement may affect the prognosis in these patients.\u003c/p\u003e","manuscriptTitle":"Management of the axilla in postmenopausal patients with cN0 hormone receptor-positive/ HER2-negative breast cancer treated with neoadjuvant endocrine therapy and its prognostic impact.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-18 23:32:06","doi":"10.21203/rs.3.rs-2394671/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2023-02-02T20:59:52+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-01-16T21:12:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-01-16T19:16:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Breast Cancer Research and Treatment","date":"2022-12-29T21:23:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-12-21T07:18:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research and Treatment","date":"2022-12-20T14:23:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c108b877-2a3f-417a-8ad7-39de7fa739ac","owner":[],"postedDate":"January 18th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T20:33:37+00:00","versionOfRecord":{"articleIdentity":"rs-2394671","link":"https://doi.org/10.1007/s10549-023-06926-y","journal":{"identity":"breast-cancer-research-and-treatment","isVorOnly":false,"title":"Breast Cancer Research and Treatment"},"publishedOn":"2023-04-12 20:27:27","publishedOnDateReadable":"April 12th, 2023"},"versionCreatedAt":"2023-01-18 23:32:06","video":"","vorDoi":"10.1007/s10549-023-06926-y","vorDoiUrl":"https://doi.org/10.1007/s10549-023-06926-y","workflowStages":[]},"version":"v1","identity":"rs-2394671","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2394671","identity":"rs-2394671","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}