Axillary surgery in patients with sentinel node macrometastases: secondary results of the randomized INSEMA trial.

Background: Axillary nodal status is an important prognostic factor in early breast cancer (eBC), guiding 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 (cN0) patients (pts). The Intergroup-Sentinel-Mamma (INSEMA) trial investigated the avoidance of sentinel lymph node biopsy (SLNB) in cN0 pts (Rando1) or the omission of completion axillary lymph node dissection (cALND) in pN1a(sn) pts (Rando2). The analysis of the first randomization demonstrated non-inferiority of omitting SLNB in cN0 patients undergoing breast-conserving surgery (BCS) concerning invasive disease-free survival (iDFS), meeting the trial's primary endpoint. Here we report the analysis of the second randomization. Study Design: The INSEMA trial was conducted between 2015 and 2019 in Germany and Austria. The first randomization of this prospective trial compared no axillary surgery with SLNB in pts with invasive eBC (tumor size ≤ 5 cm; c/iN0) scheduled for BCS, including postoperative whole-breast irradiation (WBI). This randomization was carried out in a 4:1 allocation (SLNB vs. no SLNB). Pts with 1-3 macrometastases in the SLNB arm underwent a second randomization in a 1:1 ratio, to either SLNB alone or cALND. The aim was to assess whether SLNB alone is non-inferior to cALND in terms of iDFS. The analysis of Rando2 was based on the per-protocol (PP) set. Due to fewer SLNB-positive patients than expected, the iDFS analysis for the second randomization was downgraded from a co-primary to a key secondary outcome following protocol amendment #5 (December 2018). The non-inferiority margin was defined as 5-year iDFS > 76.5% (hazard ratio (HR) < 1.271) for SLNB alone, compared to an expected 5-year iDFS of 81% for the cALND arm. Results: 485 pts were recruited for Rando2 (intention-to-treat (ITT) set: N=243 with cALND vs. N=242 with SLNB alone). After excluding 99 pts (mainly due to axillary surgery performed not per randomized arm), 386 pts (cALND: N=169, SLNB alone: N=217) were included in the PP set. The median follow-up (FU) is 74.2 months. The cALND cohort is characterized by higher rates for postoperative chemotherapy (39.8% vs. 33.6%, p=0.239), conventionally fractionated WBI (87.0% vs. 75.1%, p=0.004), tumor bed boost (88.8% vs. 80.6%, p=0.035), and regional nodal irradiation (36.0% vs. 20.6%, p=0.019) compared to the SLNB alone cohort. Analysis in the PP set was unable to demonstrate non-inferiority for SLNB alone compared to cALND, with an HR of 1.6]9 (95% CI: 0.98-2.94). Estimated 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 (log-rank p=0.058). Estimated 5-year overall survival (OS) rates are 94.9% (90.6%-97.2%) in the SLNB alone arm and 96.2% (91.7%-98.3%) in the cALND arm (log-rank p=0.663). Among the ITT set, there was also no difference in iDFS between the arms, with an HR of 1.26 (0.80-1.99) for SLNB alone compared to cALND. Estimated 5-year iDFS rates (ITT set) are 86.0% (80.6%-90.0%) with SLNB alone and 89.3% (84.3%-92.8%) with cALND, respectively (log-rank p=0.314). Locoregional recurrences (LRR) were infrequent, with 5-year cumulative incidence rates of 1.1% vs. 0.0% (p=0.405) in the SLNB alone arm compared to cALND. The safety analysis demonstrates that patients who underwent SLNB alone benefited in terms of lymphedema rate, arm mobility, and reduced arm and shoulder pain. Conclusion: No significant differences were observed between SLNB alone vs. cALND in both subsets (PP, ITT) for iDFS, OS, and LRR. These findings after a 6-year FU are representative of cN0 pts with positive SLNB and BCS; the 10-year FU data will be presented in 2029. Citation Format: T. Reimer, A. Stachs, K. Veselinovic, T. Kühn, J. Heil, S. Polata, F. Marmé, E. K. Trapp, T. Müller, G. Hildebrandt, D. Krug, B. Ataseven, R. Reitsamer, S. Ruth, H. Strittmatter, C. Denkert, I. Bekes, N. Stahl, D. Zahm, M. Thill, M. Golatta, J. Holtschmidt, M. Knauer, V. Nekljudova, S. Loibl, B. Gerber. Axillary surgery in breast cancer patients with one to three sentinel node macrometastases and breast-conserving therapy: Secondary results of the INSEMA trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS2-02.

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: 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.

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.

Axillary surgery is an established part of the management of primary breast cancer. It provides staging information to guide adjuvant therapy and potentially local control of axillary disease. Several alternative approaches to axillary surgery are available, most of which aim to spare a proportion of women the morbidity of complete axillary dissection.

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.

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

7 Background: DCIS with microinvasion (DCISM) is a lesion for which prognosis may be intermediate between that of DCIS and invasive breast cancer, but for which the role of axillary lymph node staging remains controversial. Here we report clinical characteristics and outcome in 112 patients with DCISM, with a particular focus on the role of sentinel lymph node (SLN) biopsy. Methods: From our prospective database we retrospectively identified 112 patients with a diagnosis of DCISM who had undergone SLN biopsy between 1996 and 2004 at Memorial Sloan-Kettering Cancer Center. Median follow up was 6 years. Results: We found positive SLN in 12% (14/112) of all patients, macrometastases in 2.7% (3/112) and micrometastases in 10% (11/112). We performed axillary dissection (ALND) in all patients with macrometastases (3/3), finding additional positive nodes in 66% (2/3), and in 27% of those with micrometastases (3/11), finding no additional positive nodes. Among patients with negative SLN (38% of whom received systemic therapy), there were 5 loco-regional recurrences (1 in the ipsilateral axilla, and 4 in the ipsilateral breast, all DCIS) and 4 contralateral second primary breast cancers. Among patients with positive SLN (86% of whom received systemic adjuvant therapy), there were no loco-regional or distant recurrences. Conclusions: Positive SLN were present in 12% of our patients with DCISM, none of whom experienced recurrence at 6 years’ follow up. SLN biopsy may be justified for DCISM, but is clearly most beneficial to identify a very small subset of DCISM patients (2.7%, with SLN macrometastases) who could benefit from systemic adjuvant therapy. Our data imply that between 125 and 250 SLN biopsy procedures would be required to avoid breast cancer mortality in 1 patient, and do not support the routine use of ALND for SLN-positive patients. We recommend a critical reappraisal of routine SLN biopsy for DCISM.

Recent data from clinical trials have challenged traditional thinking about axillary surgery in patients with breast cancer. To summarize evidence regarding the role of axillary interventions (surgical and nonsurgical) in breast cancer treatment and to review the association of these axillary interventions with recurrence of axillary node metastases, mortality, and morbidity outcomes in patients with breast cancer. Ovid MEDLINE (1946-July 2013), Cochrane Database of Systematic Reviews (2005-July 2013), Cochrane Database of Abstracts of Reviews of Effects (1994-July 2013), and Cochrane Central Register of Controlled Trials (1989-July 2013) were searched for publications on axillary interventions in breast cancer. Clinical trials, observational studies, and meta-analyses with at least 2-year follow-up were included. A total of 1070 publications were reviewed, 17 of which met final inclusion criteria. Partial mastectomy followed by whole breast radiation is breast-conserving therapy. For women with no suspicious, palpable axillary nodes who undergo breast-conserving therapy, there is little evidence of benefit from surgical complete axillary node dissection compared with sentinel node biopsy alone. Complete axillary node dissection in patients with no palpable lymph nodes, compared with sentinel node biopsy, provides no survival benefit and is associated with a 1% to 3% reduction in recurrence of axillary lymph node metastases, but is associated with a 14% risk of lymphedema. Surgical axillary staging via sentinel node biopsy in patients with benign axillary nodes on radiological and clinical examination helps to inform decisions regarding adjuvant systemic and radiation therapy. Patients and physicians should tailor axillary lymph node interventions to maximize regional disease control and minimize morbidity. Complete axillary lymph node dissection is indicated in patients who present with palpable or needle biopsy-proven axillary metastases, patients with positive sentinel nodes undergoing mastectomy (who do not, as a standard, receive adjuvant radiation), patients with more than 3 positive sentinel nodes undergoing breast-conserving therapy, and patients not meeting eligibility criteria for recent trials establishing the safety of sentinel node biopsy alone in patients with breast cancer and metastases in their sentinel nodes. Available evidence suggests that axillary node dissection is associated with more harm than benefit in women undergoing breast-conserving therapy who do not have palpable, suspicious lymph nodes, who have tumors 3.0 cm or smaller, and who have 3 or fewer positive nodes on sentinel node biopsy.

Background: Axillary lymph node dissection (ALND) remains the standard of care for patients with breast cancer with residual nodal disease (ypN+) after neoadjuvant chemotherapy (NAC). While the results of randomized controlled trials on the safety of omitting ALND are still awaited, retrospective studies suggest that de-escalation is already incorporated into clinical practice. This systematic review and meta-analysis aimed to evaluate oncological outcomes of sentinel lymph node biopsy (SLNB) alone versus ALND in patients with residual nodal disease after NAC. Methods: A systematic search of PubMed, Embase, and the Cochrane Library was performed. Eligible studies included randomized controlled trials and observational cohort studies of patients with clinically node-positive breast cancer who received NAC and were found to have ypN+ disease at surgery. Studies reporting outcomes of axillary recurrence, distant recurrence-free survival (DRFS), and/or overall survival (OS) were included. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing SLNB to ALND were extracted or estimated from Kaplan-Meier curves using validated methods. A random-effects meta-analysis was conducted. Results: Nine retrospective studies encompassing a total of 13,160 patients were included in the analysis. Of these, 3,831 patients underwent SLNB alone, while 9,329 underwent ALND. Axillary recurrence outcomes were reported in six studies. The pooled axillary recurrence rate was 5.91% (95% CI: 3.47%-9.92%) in the SLNB group and 5.24% (95% CI: 3.66%-7.44%) in the ALND group. SLNB was associated with a statistically significant reduction in axillary recurrence compared to ALND (HR = 0.94, 95% CI: 0.90-0.99), although the difference may not be clinically meaningful. Five studies reported DRFS with no significant difference between SLNB and ALND (HR = 0.99, 95% CI: 0.83-1.18), though substantial heterogeneity was present (I2 = 69.7%), suggesting variability that may affect outcomes. Eight studies reported OS outcomes and no significant difference in OS between the two groups (HR = 1.08, 95% CI: 0.94-1.24, p = 0.26). Notably, all these findings may reflect selection bias, as patients selected for SLNB alone may have been more likely to have favorable baseline characteristics. Conclusion: This meta-analysis of retrospective studies suggests that omission of ALND in ypN+ patients does not compromise axillary control and may be associated with comparable regional and distant control with similar survival. However, due to the inherent limitations of retrospective data—including potential selection bias and unmeasured confounding—these findings should be interpreted with caution. Prospective randomized trials are necessary to confirm the safety of omitting ALND and to identify which patients may be appropriate candidates for axillary surgery de-escalation. Citation Format: N. Polidorio, R. Frederice, G. Azevedo Gabriele Carlos, T. Dassie, R. Sousa-Barroso. De-escalation of Axillary Surgery in Patients with Residual Nodal Disease After Neoadjuvant Chemotherapy: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-03-24.

For women with breast cancer, the role of completion axillary lymph node dissection (ALND) after identification of nodal metastases by sentinel lymph node biopsy (SLNB) has been questioned. Our objectives were to assess national nodal evaluation practice patterns and to examine differences in recurrence and survival for SLNB alone versus SLNB with completion ALND. From the National Cancer Data Base (1998 to 2005), women with clinically node-negative breast cancer who underwent SLNB and who had nodal metastases were identified. Practice patterns and outcomes were examined for patients who underwent SLNB alone versus SLNB with completion ALND (median follow-up, 63 months). Of 97,314 patients, 20.8% underwent SLNB alone, and 79.2% underwent SLNB with completion ALND. In 2004 to 2005, patients were significantly more likely to undergo SLNB alone if they were older, had smaller tumors, or were treated at non-National Cancer Institute-designated cancer centers. In patients with macroscopic nodal metastases (n = 20,075 during 1998 to 2000), there was a nonsignificant trend toward better outcomes for completion ALND (v SLNB alone) after analysis was adjusted for differences between the two groups: axillary recurrence (hazard ratio [HR], 0.58; 95% CI, 0.32 to 1.06) and overall survival (HR, 0.89; 95% CI, 0.76 to 1.04). In patients with microscopic nodal metastases (n = 2,203 during 1998 to 2000), there were no significant differences in axillary recurrence or survival for patients who underwent SLNB alone versus completion ALND. Compared with SLNB alone, completion ALND does not appear to improve outcomes for breast cancer patients with microscopic nodal metastases; however, there was a nonsignificant trend toward better outcomes with completion ALND for those with macroscopic disease.

The surgical management of the axilla has undergone significant evolution during the past 20 years. The inception of the sentinel lymph node (SLN) concept and the clinical validation of lymphatic mapping and SLN biopsy (SLNB) starting in the 1990s, challenged the century-old primacy of axillary lymph node dissection (ALND) as the procedure of choice for staging the axilla and ushered us into a new era of axillary surgical management. Randomized clinical trials, evaluating SLNB with or without completion ALND in patients with operable breast cancer and negative SLN(s), established SLNB alone as the standard of care for staging the axilla in this setting. These trials established the performance characteristics of SLNB and factors that affect identification and false-negative rate and led to the refinement of the original SLN node concept. More importantly, the results from these trials provided the launching pad for the conduct of additional randomized trials evaluating SLNB alone vs. SLNB with completion ALND in patients with operable breast cancer and limited SLN involvement (micrometastases in IBCSG 23-01 or macrometastases in 1 or 2 SLNs in ACOSOG Z0011). These trials demonstrated no disease-free or overall survival advantage with completion ALND, thus expanding the use of SLNB alone in patients with limited SLN involvement. Another clinical trial (AMAROS) compared the effect of axillary radiotherapy vs. completion ALND in patients with positive SLN(s) and demonstrated equivalent oncologic outcomes between the two approaches but with less morbidity in favor of axillary radiotherapy. Thus, for patients who meet the criteria for inclusion in the ACOSOG Z11 and the IBCSG 23-01 trials, SLNB alone without completion ALND is adequate for staging the axilla. For patients who meet the criteria for inclusion in the AMAROS trial, axillary radiotherapy appears to represent a better option than completion ALND. Lastly, the increasing use of neoadjuvant chemotherapy in appropriately-selected patients with large operable breast cancer and the resulting axillary nodal down-staging in a considerable proportion of patients with axillary lymph node involvement at presentation, has led to an increased interest in the evaluation of SLNB in this setting. After a decade-old debate, the prevailing approach for patients who present with clinically negative axilla and are considered for neoadjuvant chemotherapy, is to perform SLNB after neoadjuvant chemotherapy. This approach has now also been expanded to include patients who present with clinically (or biopsy proven) involvement of the axillary nodes, become clinically node-negative after neoadjuvant chemotherapy and have negative SLNB. Several prospective trials (ACOSOG Z1071, SENTINA, SN FNAC) have recently demonstrated the feasibility and accuracy of SLNB alone in this setting. Provided that certain procedures are followed (removal of 3 or more SLNs, dual-agent lymphatic mapping, localization and removal of previously biopsied positive nodes and even the use of immunohistochemistry in the SLN evaluation), the false-negative rate of SLNB drops to below 10%. Adoption of this approach has the potential to further decrease the use of ALND in patients who present with documented axillary lymph node involvement. Citation Format: Mamounas EP. Optimal management of the axilla: A look at the evidence. [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 CS1-2.

Simple SummaryAxillary status is crucial for determining the correct local and systemic treatment. The possibility of de-escalating axillary surgery in patients with breast cancer undergoing neo-adjuvant chemotherapy is controversial. This is especially true for clinically node-positive (cN+) patients, for whom axillary lymph node dissection still represents the gold standard, in contrast to clinically node-negative (cN0) patients, for whom sentinel lymph node biopsy has become more widely accepted. Several studies have recently shown that a minimally invasive surgical approach of the axilla is safe in cN+ patients who become cN0 after neo-adjuvant chemotherapy, raising new questions about the potential benefit of this strategy. This retrospective study is aimed at assessing the reliability of this approach by comparing the characteristics and oncological outcomes (e.g., overall survival) of cN0 and cN+ patients before neo-adjuvant chemotherapy and axillary surgery type.Background: Sentinel lymph node biopsy (SLNB) has emerged as the standard procedure to replace axillary lymph node dissection (ALND) in breast cancer (BC) patients undergoing neo-adjuvant chemotherapy (NAC). SLNB is accepted in clinically node-negative (cN0) patients; however, its role in clinically node-positive (cN+) patients is debatable. Methods: We performed a retrospective analysis of BC patients undergoing NAC and SLNB. Our aim was to evaluate the clinical significance of SLNB in the setting of NAC. This was accomplished by comparing the characteristics and oncological outcomes between cN0 and cN+ patients prior to NAC and type of axillary surgery. Results: A total of 291 patients were included in the analysis: 131 were cN0 and 160 were cN+ who became ycN0 after NAC. At a median follow-up of 43 months, axillary recurrence occurred in three cN0 (2.3%) and two cN+ (1.3%) patients. However, there were no statistically significant differences in oncological outcomes (disease-free survival, distant disease-free survival, overall survival, and breast-cancer-specific survival) between cN0 and cN+ patients nor between patients treated with SLNB only or ALND. Conclusions: SLNB in the setting of NAC is an acceptable procedure with a general good prognosis and low axillary failure rates for both cN0 and cN+ patients.

The aim of this study was to assess the capacity of positron emission tomography (PET) with fluorodeoxyglucose (FDG) to determine axillary lymph node status in patients with breast cancer undergoing sentinel node (SN) biopsy. Thirty-two patients with breast cancer and clinically negative axillary nodes were recruited. All patients underwent FDG-PET before SN biopsy. After SN biopsy, all patients underwent complete axillary lymph node (ALN) dissection. The SNs were identified in all patients. Fourteen patients (43.8%) had metastatic SNs (macrometastatic in seven, micrometastatic in six, and isolated tumor cells in one). The false-negative rate of SN biopsy was 6.6% (1 in 15). FDG-PET identified lymph node metastases in 3 of the 14 patients with positive SNs. The overall sensitivity, specificity, and positive and negative predictive values of FDG-PET in the diagnosis of axillary metastasis were 20%, 100%, 100%, and 58.6%, respectively. No false-positive findings were obtained with FDG-PET. This study demonstrates the limitations of FDG-PET in the detection of ALN metastases in patients with early breast cancer. In contrast, FDG-PET seems to be a specific method for staging the axilla in breast cancer. SN biopsy can be avoided in patients with positive FDG-PET, in whom complete ALN dissection should be the primary procedure.

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.