Abstract GS2-02: Axillary surgery in breast cancer patients with one to three sentinel node macrometastases and breast-conserving therapy: Secondary results of the INSEMA trial

Background: Axillary nodal status is an important prognostic factor in breast cancer (BC), guiding (neo)adjuvant systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative patients. The replacement of axillary lymph node dissection (ALND) by sentinel lymph node biopsy (SLNB) two decades ago and later omitting completion ALND (cALND) according to the ACOSOG Z0011 criteria led to surgical de-escalation. The Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) aims to investigate whether surgical axillary staging as part of breast-conserving therapy (BCT) for early BC can be avoided without compromising oncological safety. Study Design: The INSEMA trial was conducted between September 2015 and April 2019 in Germany and Austria. This prospective, randomized trial compares no axillary surgery with standard SLNB in pts with early invasive BC (tumor size ≤ 5 cm; c/iT1–2 c/iN0) scheduled for BCT, including postoperative whole-breast irradiation. The primary objective is to assess whether no axillary surgery is non-inferior to SLNB regarding invasive disease-free survival (iDFS). Clinical non-inferiority is a hazard ratio (HR) below 1.271 when comparing the non-SLNB with the SLNB group. The randomization was carried out in 4:1 allocation (SLNB vs. no SLNB) because pN1a(sn) pts in the SLNB arm underwent a second randomization to either SLNB alone or cALND (key secondary outcome). The primary analysis is based on the per-protocol (PP) set. Adjusting for 1:4 randomization, 5230 pts (PP set) are needed. Assuming a 5% exclusion rate from the PP set, about 5505 pts must be randomized. Results: 5502 eligible pts were randomized to no SLNB (n=1101) vs. SLNB (n=4401). The drop-out rate was 6.3%, leading to an intent-to-treat (ITT) population of N=5154. After excluding 296 patients (n=252 without postoperative radiotherapy), 4858 patients (no SLNB: n=962, SLNB: n=3896) were included in the PP set. The median follow-up (FU) is 73.6 months (IQR 61.3-86.4). Patient and tumor characteristics are well-balanced between treatment arms. The median age at diagnosis was 62.0 years (range 24.0–89.0). Most pts presented with low-risk BC (78.6% pT1 stage, 98.5% hormone receptor-positive, 3.6% HER2-positive, and 3.6% G3 tumors). Significantly more pts received adjuvant chemotherapy in the SLNB arm (13.2% vs 10.7% in the no SLNB arm). The primary analysis in the PP established non-inferiority in iDFS between study arms with a HR=0.91 (95% CI: 0.73-1.14) for no SLNB to SLNB. The estimated 5-year iDFS rates are 91.9% (89.9%-93.5%) in the non-SLNB arm and 91.7% (90.8%-92.6%) in the SLNB arm. The first iDFS events (n=525, overall 10.8%) for no SLNB vs. SLNB consist of invasive locoregional recurrences (1.9% vs. 1.4%), including axillary recurrences (1.0% vs. 0.3%), invasive contralateral BCs (1.0% vs. 0.6%), distant metastases (2.7% vs. 2.7%), secondary malignancies (3.3% vs. 3.9%), and deaths (1.4% vs. 2.4%). The estimated 5-year overall survival (OS) rates are 98.2% (97.1%-98.9%) in the non-SLNB arm and 96.9% (96.3%-97.5%) in the SLNB arm. Conclusion: The INSEMA trial, enrolling 5500 pts, demonstrated that the omission of SLNB in clinically node-negative BC pts undergoing BCT resulted in a statistically significant non-inferior iDFS meeting the primary endpoint. INSEMA demonstrates oncological safety in all aspects when the axillary SLNB is omitted in cN0 patients with an early BC planned for primary BCT. This practice-changing concept is suitable for patients presenting with low-grade (G1/G2), hormone receptor-positive/HER2-negative invasive BC with tumor size up to 5 cm. Citation Format: Toralf Reimer, Angrit Stachs, Kristina Veselinovic, Thorsten Kuhn, Jorg Heil, Silke Polata, Frederik Marme, Thomas Muller, Guido Hildebrandt, David Krug, Beyhan Ataseven, Roland Reitsamer, Andrea Stefek, Carsten Denkert, Inga Bekes, Dirk Michael Zahm, Marc Thill, Michael Golatta, Johannes Holtschmidt, Michael Knauer, Valentina Nekljudova, Sibylle Loibl, Bernd Gerber on behalf of the INSEMA investigators. No axillary surgery versus axillary sentinel lymph node biopsy in patients with early invasive breast cancer and breast-conserving surgery: Final primary results of the Intergroup-Sentinel-Mamma (INSEMA) trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS2-07.

Background: Currently, axillary surgery for breast cancer is considered as staging procedure that does not seem to influence breast cancer mortality, since the risk of developing metastasis depends mainly on the biological behaviour of the primary. Based on this, the postsurgical therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement. Trial design: The goal of INSEMA is to show that early-stage breast cancer patients with reduced extent of axillary surgery are not inferior regarding invasive disease-free survival (IDFS) outcome. Patients with planned breast-conserving surgery (BCS) will be first randomized (1:4 ratio) to either no axillary surgery or axillary sentinel lymph node biopsy (SLNB). Patients with SLNB and pN+(sn) status will be secondly randomized (1:1 ratio) to either SLNB alone or completion axillary lymph node dissection (ALND) in cases with less than three involved nodes (one or two macrometastases). Primary objective: -IDFS after BCS (non-inferiority question) Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy) -Age at least 35 years -Preoperative imaging techniques with estimated tumor size of maximal 5 cm (iT1/iT2 irrespective of hormone sensitivity or HER2 status) -Clinically and sonographically tumor-free axilla prior to core biopsy -In cases with cN0 and iN+, a negative core biopsy or fine needle aspiration biopsy of the suspected lymph node is required -No clinical evidence for distant metastasis (M0) -Planned breast-conserving surgery (R0 resection) with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Statistics: Assumptions for first randomization: -The 5-year IDFS for women with cN0/iN0 axillary lymph nodes and T1/T2 disease is considered to be 88% -Clinical non-inferiority is defined as the non-SLNB group having a 5-year IDFS of not less than 85% and if the hazard ratio (HR) is less than 1.271 when compared with the SLNB group The total number of patients in the per-protocol set of the first randomization must be increased from 3,796 to 5,940 (936 events) due to unequal-sample-size design. Assumptions for second randomization: -The 5-year IDFS for women with pN+(sn) axillary lymph nodes (1-2 macrometastases) and T1/T2 disease is considered to be 81% -Clinical non-inferiority is defined as the SLNB alone group having a 5-year IDFS of not less than 76.5% and if the hazard ratio (HR) is less than 1.271 when compared with the completion ALND group The total number of patients to be included into the per-protocol set for the second randomization will be approximately 1,968. Finally, the calculated total case number for per-protocol analyses is 6,740 (5,940 German and 800 Austrian patients), the expected total number of randomized patients is 7,095. Time lines: -First patient in: September 2015 -Last patient in: August 2019 -Final analysis: End of 2024 Funding by Deutsche Krebshilfe (grant no. 110580). Citation Format: Reimer T, von Minckwitz G, Loibl S, Hildebrandt G, Denkert C, Nekljudova V, Kundt G, Becker D, Gerber B. Comparison of axillary sentinel lymph node biopsy versus no axillary surgery in patients with early-stage invasive breast cancer and breast-conserving surgery: A randomized prospective surgical trial. The intergroup-sentinel-mamma (INSEMA)-trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-02-01.

Background:Based on randomized controlled trials demonstrating no survival benefit of axillary dissection in elderly breast cancer patients, the SSO/Choosing Wisely campaign recommended against the routine use of sentinel lymph node biopsy (SLNB) in clinically node negative patients aged ≥70 with estrogen receptor (ER) positive breast cancer in 2016. SLNB is still performed in >80% of such patients and we have previously shown that at our institution, SLNB positivity influences adjuvant therapy decisions in this population. In this study, we sought to validate the association of SLNB positivity and adjuvant treatment in a larger population-based cohort, and to evaluate the impact of this finding on oncologic outcomes. Methods:The Breast Cancer Outcome Unit (BCOU) prospectively collects demographic, pathologic, treatment and outcomes data on all patients referred to BC Cancer with breast cancer in British Columbia, Canada. Female patients aged ≥70 with newly diagnosed estrogen receptor-positive invasive breast cancer who underwent SLNB from 2010-2016 were included. Patients with HER2-positive disease or those treated with neoadjuvant therapy were excluded. Multivariable analysis was used to assess the effect of SLNB positivity on adjuvant treatment. Overall survival (OS) and breast cancer specific survival (BCSS) were assessed using Kaplan-Meier analysis and Cox regression was used to assess contribution of SLNB positivity and adjuvant treatment. A nomogram was created to model the effect of nodal positivity and adjuvant treatment on BCSS. Results:We identified 2580 patients who met study criteria with a median age of 75 and a median tumor size of 15 mm. SLNB was positive in 23%. Sixty-seven percent of patients had breast conserving surgery (BCS) and 62% of patients had RT (BCS 79%, mastectomy 25%). As systemic therapy 5% of patients had chemotherapy (CT) and 78% of patients had hormone therapy (HT). Use of adjuvant therapies was associated with SLNB positivity: Systemic therapy (HR = 2.4, 95% CI: 1.84-3.14, p <0.0001), RT (HR = 4.94, 95% CI: 3.91-6.25, p <0.0001) and nodal RT (HR = 61.4, 95% CI: 26.6-141.7, p <0.0001). The 5-year OS was 86% and BCSS was 96% with a median follow-up of 4.33 years (95% CI 4.21-4.47 years). There was improved BCSS with receipt of HT (HR 0.51 95% CI 0.301-0.875, p=0.0142) and worse BCSS with grade 3 vs grade 1 disease (HR 4.09, 95% CI 2.06-8.10, p<0.0001). Age, tumor size, status of SLNB and use of RT were not significant prognostic variables. Patients with a positive SLNB who did not receive any adjuvant therapy had lower BCSS (HR 3.22 95% CI 1.235-8.418, p=0.0168) than those with a negative SLNB. However, amongst those who received any combination of CT, HT and RT, there was no significant difference in BCSS regardless of nodal status. A nomogram was developed incorporating tumor size, grade, SLNB status and adjuvant treatment. Using the nomogram, patients aged 75-79 with T1, grade 1-2 tumors, with or without positive SLNB and treated with or without adjuvant therapy had 5-year BCSS ≥95%. The nomogram also indicated that 5-year BCSS was similar for patients with positive and negative SLNB for all combinations of tumor features when patients received HT. Conclusions:In this modern, population-based cohort of patients over 70 with ER-positive breast cancer, 5-year BCSS was excellent at 96%. Although the use of adjuvant treatment was associated with a positive SLNB, BCSS was not changed based on nodal status when patients received HT. Our results support the Choosing Wisely recommendations; SLNB can be safely omitted in elderly patients willing to take HT, and we advocate that SLNB can be omitted in low-risk patients aged ≥75 even in the absence of planned HT. Citation Format: Elaine McKevitt, Rona Cheifetz, Kimberly DeVries, Alison Laws, Rebecca Warburton, Lovedeep Gondara, Caroline Lohrisch, Alan Nichol. Sentinel node biopsy should not be routine in older patients with ER positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD4-02.

With the purpose of minimizing arm lymphedema after axillary staging surgeries in breast cancer patients, the axillary reverse mapping (ARM) technique has been developed to identify and preserve arm drainage system during axillary surgery. This study aimed to clarify risk factors for metastasis in arm lymphatic drainage system in breast cancer patients with clinically negative axillary nodes. Sixty-nine patients who underwent successful both sentinel lymph node (SLN) biopsy (SLNB) and ARM from October 2009 to August 2010 were enrolled in this study. Radioactive tracer was used for SLN localization and blue dye was used for ARM. All of the identified SLNs and ARM nodes were sent for pathological assessment. ARM nodes metastasis occured in 6 of 69 patients. Age, pathological tumor size (pT) and pathological lymph node status (pN) were not associated with ARM nodes metastasis (P>0.01). Interestingly, in these 6 patients, all metastatic ARM nodes coincided with SLN-ARM nodes (hot SLN and blue ARM node were the same lymph node). In 50 of 69 patients whose ARM nodes did not coincided with SLNs, all ARM nodes were negative, even in 12 patients with metastatic SLNs. Crossover between breast and ipsilateral arm lymphatic drainage system contributes for ipsilateral arm lymph node metastasis. When ARM and SLNB are simultaneously performed in a patient, selectively preservation of the ARM nodes that do not coincided with SLNs would be safe, even if the SLNs are positive. Pathological lymph node status does not account for the occurrence of metastasis in ARM nodes. ARM nodes could be preserved safely, independent of the pathological lymph node status.

Background: Currently, axillary surgery for breast cancer is considered as staging procedure that does not seem to influence breast cancer mortality, since the risk of developing metastasis depends mainly on the biological behaviour of the primary. Based on this, the postsurgical therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement. Trial design: The goal of INSEMA is to show that early-stage breast cancer patients with reduced extent of axillary surgery are not inferior regarding invasive disease-free survival (IDFS) outcome. Patients with planned breast-conserving surgery (BCS) will be first randomized (1:4 ratio) to either no axillary surgery or axillary sentinel lymph node biopsy (SLNB). Patients with SLNB and pN+(sn) status will be secondly randomized (1:1 ratio) to either SLNB alone or completion axillary lymph node dissection (ALND) in cases with less than three involved nodes (one or two macrometastases). Primary objective: -IDFS after BCS (non-inferiority question) Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy) -Age at least 35 years -Preoperative imaging techniques with estimated tumor size of maximal 5 cm (iT1/iT2 irrespective of hormone sensitivity or HER2 status) -Clinically and sonographically tumor-free axilla prior to core biopsy -In cases with cN0 and iN+, a negative core biopsy or fine needle aspiration biopsy of the suspected lymph node is required -No clinical evidence for distant metastasis (M0) -Planned breast-conserving surgery (R0 resection) with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Statistics: The calculated total case number for per-protocol analyses is 6,740 (5,940 German and 800 Austrian patients), the expected total number of randomized patients is 7,095. Time lines: -First patient in: September 2015 -Last patient in: August 2019 -Final analysis: End of 2024 Present accrural: In June 2016, more than 1.000 patients were recruited in Germany and Austria. Citation Format: Reimer T, von Minckwitz G, Loibl S, Hildebrandt G, Nekljudova V, Schneider-Schranz C, Gerber B. Comparison of axillary sentinel lymph node biopsy versus no axillary surgery in patients with early-stage invasive breast cancer and breast-conserving surgery: A randomized prospective surgical trial. The Intergroup-Sentinel-Mamma (INSEMA)-trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-04-02.

To assess the morbidity after sentinel lymph node (SLN) biopsy compared with SLN and completion level I and II axillary lymph node dissection (ALND) in a prospective multicenter study. ALND after breast cancer surgery is associated with considerable morbidity. We hypothesized: 1) that the morbidity in patients undergoing SLN biopsy only is significantly lower compared with those after SLN and completion ALND level I and II; and 2) that SLN biopsy can be performed with similar intermediate term morbidity in academic and nonacademic centers. Patients with early stage breast cancer (pT1 and pT2 <or= 3 cm, cN0) were included between January 2000 and December 2003 in this prospective Swiss multicenter study. All patients underwent SLN biopsy. In all patients with SLN macrometastases and most patients with SLN micrometastases (43 of 68) or isolated tumor cells (11 of 19), a completion ALND was performed. Postoperative morbidity was assessed based on a standardized protocol. SLN biopsy alone was performed in 449 patients, whereas 210 patients underwent SLN and completion ALND. The median follow-ups were 31.0 and 29.5 months for the SLN and SLN and completion ALND groups, respectively. Intermediate-term follow-up information was available from 635 of 659 patients (96.4%) of enrolled patients. The following results were found in the SLN versus SLN and completion ALND group: presence of lymphedema (3.5% vs. 19.1%, P < 0.0001), impaired shoulder range of motion (3.5% vs. 11.3%, P < 0.0001), shoulder/arm pain (8.1% vs. 21.1%, P < 0.0001), and numbness (10.9% vs. 37.7%, P < 0.0001). No significant differences regarding postoperative morbidity after SLN biopsy were noticed between academic and nonacademic hospitals (P = 0.921). The morbidity after SLN biopsy alone is not negligible but significantly lower compared with level I and II ALND. SLN biopsy can be performed with similar short- and intermediate-term morbidity in academic and nonacademic centers.

Surgeons have routinely removed ipsilateral axillary lymph nodes from women with breast cancer for over 100 years. The procedure provides important staging information, enhances regional control of the malignancy and may improve survival. As screening of breast cancer has increased, the mean size of newly diagnosed primary invasive breast cancers has steadily decreased and so has the number of women with lymph node metastases. Recognising that the therapeutic benefit of removing normal nodes may be low, alternatives to the routine level I/II axillary lymph node dissection have been sought. A decade ago sentinel lymph node biopsy (SLNB) was introduced. Because of its high accuracy and relatively low morbidity, this technique is now widely used to identify women with histologically involved nodes prior to the formal axillary node dissection. Specifically, SLNB has allowed surgeons to avoid a formal axillary lymph node biopsy in women with histologically uninvolved sentinel nodes, while identifying women with involved sentinel nodes who derive the most benefit from a completion axillary node dissection. Despite the increasing use of SLNB for initial management of the axilla in women with breast cancer, important questions remain regarding patient selection criteria and optimal surgical methods for performing the biopsy. This article discusses the evolution of axillary node surgery for women with breast cancer.

Background: Despite increasing evidence disfavoring axillary lymph node dissection (ALND) for locoregional control, it remains part of guidelines for breast cancer (BC) treatment. In an attempt to re-evaluate standard local therapy, the INSEMA trial was designed to assess non-inferiority of avoiding sentinel lymph node biopsy (SLNB) or completion ALND (cALND) in early-stage clinically node-negative BC patients. Here we present PROs from the INSEMA trial. Methods: INSEMA (NCT02466737) investigates non-inferiority of invasive disease-free survival (iDFS) after no axillary surgical staging versus SLNB (first randomization 1:4) in patients with clinically node-negative BC (tumor size ≤5 cm) and primary breast-conserving surgery (BCS). In case of pN1a(sn) in the SLNB arm, patients underwent a second randomization to either SLNB alone or cALND (1:1). PROs were assessed at baseline (pre-surgery) and at 1, 3, 6, 12, and 18 months after final axillary surgery using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) and its breast cancer (BR23) module. Higher scores of C30 and BR23 (range 0-100) indicate better functioning and global health status (GHS)/quality of life (QoL) or worse symptom severity, respectively. The QoL scores were compared using the Mann-Whitney U test based on the safety set. Results: Between September 2015 and April 2019, 5,502 patients were recruited for the 1st randomization and 5,173 of them were included in the intent-to-treat set (4,138 SLNB vs 1,035 no SLNB). Patient and tumor characteristics were well-balanced between treatment arms. Median age at diagnosis was 62.0 years (range 24.0 - 89.0). Overall, recruited patients presented with low-risk BC marked by 85.6% clinically stage T1, 98.5% hormone-receptor positivity, 2.4% HER2-positivity, and 3.7% G3 tumors. The majority (73.5%) had an invasive carcinoma of no special type (72.8% in SLNB vs 76.0% in no SLNB arm) and 87.0% had Ki-67 ≤ 20%. Questionnaire completion response remained high throughout the trial: n=3,915 (75.7%) returned questionnaires at 1 month after final axillary surgery, n=3,938 (76.1%) at 3 months, n=4,024 (77.8%) at 6 months, n=3,907 (75.5%) at 12 months, and n=3,637 (70.3%) at 18 months. All QoL baseline parameters regarding GHS, functional scales, and symptom scales/items were well-balanced between arms (total 4,117 SLNB vs 1,056 no SLNB as treated; 270 of 4,117 received cALND). There were significant differences for the BRBS (breast symptoms) and BRAS (arm symptoms) scores favoring the no SLNB group in all post-baseline assessments Patients in the SLNB group showed persistent higher scores for BRAS (differences in mean values ≥5.0 points at all times of assessment) including pain, arm swelling, and impaired mobility in all postoperative visits with the highest difference at 1 month after final surgery (mean scores, 23.6 vs. 12.8, p&amp;lt;0.001). Differences between treatment arms regarding BRBS including pain, breast swelling, hypersensitivity, and other skin problems showed a smaller range, but still a continuous trend for improved QoL in the no SLNB arm. Scoring of the QLQ-C30 questionnaire revealed no relevant differences between the treatment groups postoperatively. Conclusions: This is one of the first randomized trials investigating the omission of SLNB in clinically node-negative patients and the first to report QoL data. Patients with no SLNB benefitted regarding arm symptoms/functioning while no relevant differences in other QoL scales were seen. Data for the primary outcome of the study (iDFS) are expected for the end of 2024. Citation Format: Bernd Gerber, Angrit Stachs, Kristina Veselinovic, Silke Polata, Thomas Müller, Thorsten Kühn, Jörg Heil, Beyhan Ataseven, Roland Reitsamer, Guido Hildebrandt, Michael Knauer, Michael Golatta, Andrea Stefek, Dirk-Michael Zahm, Marc Thill, Valentina Nekljudova, David Krug, Fenja Seither, Sibylle Loibl, Toralf Reimer. Patient-reported outcomes (PROs) for the intergroup sentinel mamma study (INSEMA, GBG75, ABCSG43): Persistent impact of axillary surgery on arm and breast symptoms in early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-03.

Multidisciplinary considerations in the treatment of triple-negative breast cancer.

The sub-study of the INSEMA trial (randomization-2) compares completion axillary lymph node dissection (cALND) with sentinel lymph node biopsy (SLNB) alone in cN0 patients with T1/T2 invasive breast cancer and one to three sentinel node macrometastases undergoing upfront breast-conserving surgery. The key secondary objective is to assess whether the SLNB-alone arm is non-inferior to cALND in terms of invasive disease-free survival (iDFS). Finally, 485 patients were recruited, and 386 patients (cALND: N = 169, SLNB alone: N = 217) were included in the per-protocol set. The median follow-up is 74.2 months. The 5-year iDFS analysis in the per-protocol set demonstrates a non-significant difference between study arms, with a hazard ratio (HR) of 1.69 (95% CI: 0.98-2.94) for SLNB alone compared to cALND. The 5-year iDFS rates are 86.6% (81.0%-90.7%) in the SLNB-alone arm and 93.8% (88.7%-96.6%) in the cALND arm (P = 0.058). The 5-year overall survival rates are 94.9% (90.6%-97.2%) in the SLNB-alone arm and 96.2% (91.7%-98.3%) in the cALND arm (P = 0.663). Locoregional recurrences (LRR) were infrequent, with 5-year incidence rates of 1.1% versus 0.0% (P = 0.405) in the SLNB-alone arm compared to cALND. In summary, no significant differences were observed between SLNB alone versus cALND for iDFS, overall survival, and LRR. Trial registration number: NCT02466737.

Paget's disease of the breast is an uncommon presentation of breast malignancy, accounting for 1-3% of all the breast tumors and presents in different histopathologic patterns: in association with an underlying invasive or non invasive carcinoma, or without any underlying neoplasia. In the literature, different methods are used for the treatment. Mastectomy with or without axillary dissection has been considered as the standard treatment procedure for many years. Several studies have already shown that breast conservation with radiation therapy is an oncologically safe option. Regarding the axillary approach, several studies have documented the presence of positive sentinel lymph node even in Paget's disease alone. The objective of this study was to retrospectively analyze outcome of patients affected by Paget's breast disease and to define our institutional experience. Between May 1996 and February 2003, 114 patients with confirmed Paget's disease of the breast were retrieved and underwent surgery at the European Institute of Oncology of Milan, Italy. The median age of the patients was 54 years at the time of the diagnosis. In our study, the histopathological examination of the operated specimen revealed one hundred seven patients with Paget's disease associated with an underlying invasive or non invasive carcinoma, and seven patients without underlying carcinoma. Patients underwent either conservative breast surgery or mastectomy, with or without sentinel lymph node biopsy and/or axillary surgery. Each patient was evaluated after surgery at a multidisciplinary meeting to selecting systemic therapy. Seven patients had "pure" Paget's disease of the breast and one hundred seven had the disease associated with an underlying carcinoma. As surgical techniques 71 mastectomies and 43 breast conserving surgeries have been performed. Complete axillary dissection was done in patients with clinically positive lymph node and/or sentinel lymph node biopsy positive. Sentinel lymph node biopsy was performed in nineteen patients with invasive component and five were positive and underwent axillary dissection. Eleven sentinel lymph node biopsies were done in patients with non invasive component and none of them was positive. Adjuvant systemic therapies were based on the final tumor, node and metastasis stage: thirty patients received adjuvant chemotherapy alone, fourteen received endocrine treatment alone, twenty-six patients were evaluated to receive both chemo and endocrine therapy. The median duration of follow up was 73 months and was updated in the last 6 months. Five patients developed local recurrence, one had regional recurrence, another two had loco-regional recurrences and fourteen had distant metastasis as a first event. Malignancy-related deaths were censored in the statistical analyses cancer for and due to another tumor in eleven patients. Additionally, deaths were not related to malignancy totally in thirteen patients. Screening examination and imaging techniques are fundamental. Breast conserving surgery combined with breast irradiation for patients with invasive and non invasive breast carcinoma has become the treatment of first choice. All surgical conservative approaches should include the complete nipple-areolar complex and margins of resected specimen free of tumor. Thanks to the evolution of the conservative approach, good cosmetic result can be obtained. To be informed about the axillary lymph node status and to avoid the patient to have a second surgical approach, sentinel lymph node biopsy should be performed.

P107. Can axillary lymph node clearance be avoided in select sentinel lymph node positive patients?

[Background] Axilla surgery in node-positive breast cancer is dramatically changing from axillary lymph node dissection (ALND) to sentinel node biopsy (SNB). From the results of ACOSOG Z0011, IBCSG23-01 and AMAROS trials, adjuvant therapy and regional node irradiation could reduce regional lymph node recurrence for sentinel node-positive breast cancer patients. However, optimal indication of SNB alone remains uncertain. Trial design: To evaluate the outcome of sentinel node-positive breast cancer patients, the Japanese Society for Sentinel Node Navigation Surgery (SNNS) conducted a prospective cohort study in 2013 (UMIN000011782, Jpn J Clin Oncol, p.876-9, 2014). [Eligibility criteria] For eligible patients, SNB was performed or scheduled after 1 January 2012. Then 1 to 3 positive micrometastases or macrometastases in sentinel lymph nodes are confirmed by histological or molecular diagnosis. Primary chemotherapy before or after SNB is also acceptable for registration. [Specific aims] The primary endpoint is the 5-year recurrence rate of regional lymph node in patients treated with SNB alone. The secondary endpoint is the 5-year overall survival rate of this cohort. Patients treated with SNB followed by ALND are also registered simultaneously to compare the prognosis. The propensity score matching (PSM) is used to make the distributions of baseline risk factors comparable. [Statistical method] Based on an estimated recurrence rate of 5% at 5 years among patients treated with SNB alone, 240 patients are needed to give a 80% power to reject the null hypothesis that the recurrence rate is 10% with a one-sided type I error rate of 2.5%. If we consider that some patients will be lost to follow-up or become ineligible, a total of 250 patients will be needed to comprise the sample. [Present accrual] Eight hundred and eighty patients who underwent SNB alone or SNB followed by ALND were registered from 27 participating institutes between 2013 and 2016. Data cleaning is being performed. Patient's background and PSM will be reported. Citation Format: Imoto S, Saito Oba M, Masuda N, Nagashima T, Wada N, Takashima T, Kitada M, Kawada M, Hayashida T, Taguchi T, Aihara T, Miura D, Toh U, Yoshida M, Sugae S, Yoneyama K, Matsumoto H, Jinno H, Sakamoto J. Observational study of axilla treatment for breast cancer patients with 1 to 3 positive micrometastases or macrometastases in sentinel lymph nodes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-01-01.

To assess whether the risk for nonsentinel node metastases may be predicted, thus sparing a subgroup of patients with breast carcinoma and a positive sentinel lymph node (SLN) biopsy completion axillary lymph node dissection (ALND). The SLN is the only involved axillary lymph node in the majority of the patients undergoing ALND for a positive SLN biopsy. A model to predict the status of nonsentinel axillary lymph nodes could help tailor surgical therapy to those patients most likely to benefit from completion ALND. All the axillary sentinel and nonsentinel lymph nodes of 1228 patients were reviewed histologically and reclassified according to the current TNM classification of malignant tumors as bearing isolated tumor cells only, micrometastases, or (macro)metastases. The prevalence of metastases in nonsentinel lymph nodes was correlated to the type of SLN involvement and the size of the metastasis, the number of affected SLNs, and the prospectively collected clinicopathologic variables of the primary tumors. In multivariate analysis, further axillary involvement was significantly associated with the type and size of SLN metastases, the number of affected SLNs, and the occurrence of peritumoral vascular invasion in the primary tumor. A predictive model based on the characteristics most strongly associated with nonsentinel node metastases was able to identify subgroups of patients at significantly different risk for further axillary involvement. Patients with the most favorable combination of predictive factors still have no less than 13% risk for nonsentinel lymph node metastases and should be offered completion ALND outside of clinical trials of SLN biopsy without back-up axillary clearing.

Recent data suggest that axillary lymph node dissection (ALND) may be unnecessary for patients with positive sentinel lymph node biopsy (SLNB) receiving whole-breast irradiation (ACOSOG Z0011). The purpose of this study was to use decision analysis with simulated patients to determine subgroups with positive SLNB who may still benefit from ALND. We performed a decision analysis simulating axillary recurrence (ALR) risk, lymphedema, and quality of life following breast-conserving surgery (BCS) with positive SLNB and either completion ALND and whole-breast radiation (ALND + BRT) or breast radiation (BRT) alone. Simulated patients were divided into two risk groups based on the likelihood of disease in non-sentinel axillary nodes after positive SLNB: those with risk 30-60 % ("high-risk") and those with risk under 30 % ("low-risk," similar to average Z0011 patients). In simulated patients aged 55, BRT alone resulted in 1 month of additional QALE in the low-risk group versus ALND + BRT, while ALND + BRT resulted in 9.7 months of additional QALE in the high-risk group versus BRT alone. Overall survival was similar at 5 years in this simulation with either treatment in both groups, but ALND + BRT was superior to BRT alone at 20 years in the high-risk group (42 vs. 38 %). In the low-risk group, BRT alone is preferable unless ALR risk with BRT is greater than 1.6 % or lymphedema risk with ALND is under 10 %. Patients eligible for Z0011 but at a higher risk of residual nodal disease following BCS and positive SLNB may benefit from ALND + BRT, rather than BRT alone.