ACOSOG Z0011 Trial Research Articles

A nomogram to predict the risk of axillary upstaging in patients with Z0011-eligible breast cancer.

e12606 Background: ACOSOG Z0011 trial showed that in early cT1-2N0 breast cancer patients with 1-2 positive lymph nodes in sentinel lymph node biopsy (SLNB) can safely omit axillary lymph node dissection (ALND) without compromising local control and long-term survival. Although it is widely accepted worldwide, controversy and concerns remain that the incidence of non-sentinel lymph node metastasis may lead to pathological lymph node (pN) upstaging and insufficient systemic treatment. This study aims to identify risk factors for having ≥4 metastatic lymph node (pN2-3) in patients who met Z0011 criteria and received SLNB. Methods: This is a retrospective study enrolled 733 cT1-2N0 breast cancer patients with 1-2 positive SLNs treated between 2011-2022 at Sun Yat-sen Memorial Hospital. All patients had received SLNB followed by ALND. Patients included were divided into the training and validation sets at a 7:3 ratio. Differences were compared between pN1(1-3 LN+) and pN2-3(≥4 LN+) in training set using either t test or chi-squared test. Multivariate logistic regression was conducted to identify risk factors for pN upstaging and to form the basis of a predictive nomogram. The validation was processed in the other validation set and nomogram performance was evaluated using the area under ROC curve (AUC). Results: Among the 733 patients enrolled, 127 (17.3%) patients had pN upstaging (pN2-3) after ALND. There was a big difference of pN upstaging between the patients with 1 (47/511, 9.2%) and 2 (80/222, 36%) positive SLNs. 488 patients were allocated to the training set, among which 18.2% had pN upstaging. In univariate analysis, pN were differed by cT stage, axillary ultrasound appearance, histological grade, molecular subtype, Ki67, lymph vascular invasion, pathological tumor size, SLN metastasis type (micrometastasis or macrometastasis), positive SLN numbers and negative SLN numbers. Multivariate logistic analysis resulted six independent risk factors associated to pN upstaging: ultrasound suspicious node (OR=1.93; 95% CI: 1.08-3.47), positive lympho-vascular invasion (OR=2.27; 95% CI: 1.25-4.13), larger tumor size (OR=2.07; 95% CI: 1.15-3.73), SLN macro-metastasis (OR= 9.15; 95% CI: 1.07-78.13), two positive SLNs (OR= 6.59; 95% CI:3.70-11.76) and less negative SLN number (OR=1.54; 95% CI: 1.22-1.89). These factors were used to construct a predictive nomogram, exhibiting excellent performance with AUC values of 0.819 and 0.827 in the training and validation cohorts respectively. Conclusions: The Z0011-eligible patients with two positive SLNs may have a high risk of pN upstaging and need to be cautious to spare ALND. A practical nomogram is helpful to identify patients at high risk of pN upstaging and avoid insufficient systemic treatment.

Abstract PS01-03: What to expect from the No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS] trial (KBCSG-21): Clinicopathologic characteristics and axillary lymph node status of enrolled patients

Abstract Purpose: The primary role of sentinel lymph node biopsy (SLNB) for early breast cancer (BC) is axillary staging. In terms of clearance of axillary disease or prevention of recurrence, its role may be limited considering the low axillary recurrence rate of less than 2% even though false-negative rates are 5-10% and the 25% additional axillary lymph node (ALN) detection in the ALND arms of the ACOSOG Z0011 and AMAROS trials. The NAUTILUS trial (NCT04303715) randomized cT1-2/N0 BC patients planned for breast-conserving surgery to evaluate the non-inferiority of omitting SLNB regarding 5-year invasive disease-free survival. The secondary endpoints are overall survival, distant metastasis-free survival, axillary recurrence rate, and quality of life of the patients. We aimed to investigate the clinicopathologic characteristics and ALN status of the subjects enrolled in the NAUTILUS trial. Methods: NAUTILUS trial randomized 1,734 subjects into SLNB or no-SLNB arms from September 2020 to October 2022. Axillary ultrasonography was mandatory to determine clinical N0, defined as no suspicious ALN or no tumor on ultrasound-guided biopsy of suspicious ALN. Clinicopathologic variables and the ALN status of the SLNB arm were analyzed. Results: Among 1,734 enrolled subjects, 828 (50.3%) and 818 (49.7%) subjects in the SLNB and no-SLNB arms, respectively, were included for analysis. Clinical and pathologic T stage, hormonal receptor/HER2 status, histologic grade, age, menopausal status, and Ki-67 were evenly distributed between the two groups (p = 0.554, 0.350, 0.056, 0.369, 0.623, 0.725 and 0.214, respectively). Median age was 55.3 (range, 48.0-62.0) years, and 661 (40.2%) were premenopausal. Overall, 30 (1.8%), 1,382 (84.0%), and 229 (13.9%) subjects were pTmic, pT1, and pT2, respectively, and median tumor size was 1.3 cm (range, 0.1-5.0). In the SLNB group, 94 (11.4%) had ALN metastasis, of which 9 (1.1%), 78 (9.4%), and 5 (0.6%) were pN1mic, pN1, and pN2-3, respectively (Table 1). According to pathologic tumor size, 5.8% (16/279), 11.4% (48/421), and 23.8% (30/126) were ALN positive for ≤ 1.0 cm, >1.0cm & ≤ 2.0 cm, and > 2.0 & ≤ 5.0 cm, respectively. The clinical and pathologic tumor size distribution among subjects with ALN metastasis were 23 (24.5%), 43 (45.7%), 9 (9.6%) and 16 (17.0%), 48 (51.1%), 30 (31.9%), respectively, for ≤ 1.0 cm, >1.0cm & ≤ 2.0 cm, and > 2.0 & ≤ 5.0 cm (Table 2). Among them, 12 (12.8%) received subsequent ALND. There was no difference in ALN metastasis rate according to molecular subtype, histologic grade, age, menopausal status, and Ki-67 (p= 0.812, 0.204, 0.671, and 0.101, respectively). Conclusions: The NAUTILUS trial completed enrollment of 1,734 subjects, among which 1,646 are available to analyze basic clinicopathologic characteristics. The trial included 229 (13.9%) pT2 and 661 (40.2%) premenopausal subjects and is expected to show the impact of SLNB omission in these subgroups. Data lock is expected in October 2027. Patients characteristics SLNB, sentinel lymph node biopsy; LVI, lymphovascular invasion; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; HER2, anti-human epidermal growth factor-2; BCS, breast conserving surgery; TM, total mastectomy; ALND, axillary lymph node dissection Basic characteristics for sentinel lymph node biopsy group a revealed no lymph node metastasis by fine needle aspiration or gun biopsy ALN, axillary lymph node; LN, lymph node Citation Format: Jai Min Ryu, Han-Byoel Lee, Sei Hyun Ahn, Il-Yong Chung, Seeyoun Lee, Seho Park, Woosung Lim, Joon Jeong, Jeong Eon Lee, Eunhye Kang, Ji Hyun Chang, Jung Min Chang, Woo Kyung Moon, Wonshik Han, Eun-Kyu Kim. What to expect from the No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS] trial (KBCSG-21): Clinicopathologic characteristics and axillary lymph node status of enrolled patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS01-03.

Abstract PO3-17-09: Outcome after the introduction of personalized treatment for axilla in patients with clinically node-negative early breast cancer

Abstract Background : After the results of ACOSOG Z0011 and AMAROS trials were reported, axillary treatment has been promoted to de-escalation. For clinically negative cases of axillary lymph node metastasis (cN0), axillary dissection (Ax) has been the standard treatment when sentinel lymph node (SN) metastasis is positive. In our hospital, for patients with cN0, if SN macro metastasis is positive, Ax or irradiation (RT) is selected after sufficient explanation to the patients. Five years have passed since the introduction of treatment selection for the axilla, we examined treatment outcomes retrospectively. Methods : The subjects were 1376 patients who underwent SN biopsy for primary breast cancer with cN0 at our hospital from October 2004 to December 2018 (median observation period 79 months). Cases who underwent preoperative chemotherapy were excluded. We have introduced the treatment choice system since December 2015, and compared prognosis (local recurrence, distant recurrence and breast cancer specific death) before and after introduction using the log-rank test. Results : There were 947 cases before introduction of treatment choice system (pre group) and 429 cases after introduction (post group). The median observation period for each group was 91 months and 41 months. The maximum observation period post group was 67 months, then we compared the number of events in patients with observation period less than 67 months in pre group. There was no significant difference between two groups (Pre/Post) in terms of age (p=0.52), menopausal status (p=0.90), invasion of primary lesion (p=0.19), biology and SN metastasis status (p=0.41). There were 54 patients (12.6%) in pre group and 135 (14.3%) patients in post group had positive sentinel lymph nodes. In post group, 33 patient (61.1%) were macrometastasis of SN, 28 of whom underwent Ax and 5 underwent RT. Local recurrence was 4 cases (1.7%) in pre group, 9 cases (2.1%) in post group (p=0.84), distant recurrence was 13 cases (5.6%) and 5 cases (1.2%) (p=0.0002), and breast cancer specific death was 8 cases (0.8%) and 1 case (0.2%) (p=0.0003), respectively. Discussion : There was no significant difference in local recurrence rate within 67 months, but were poor prognosis in pre introduction group for distant metastasis and breast cancer specific survival. In the results of this study, there was no significant difference in local recurrence, but the prognosis for distant recurrence and breast cancer-specific death was poor in the before introduction group. The median observation period in the post introduction group was 47 months, and late recurrence of ER-positive breast cancer occurs later. It is necessary to continue the study by extending period and accumulation cases. Conclusion : For cN0 cases, if the case is suitable, we introduced the treatment choice system that allows omitting Ax by performing radiotherapy in SN macrometastasis positive patients. After introduction, there was no increase in the relapse rate after introduction in the short term. Appropriate case selection allowed the safety introduction of individualizes treatment for axilla. Citation Format: Mai Tomiguchi, Kaori Hidaka, Lisa Goto-Yamaguchi, Ayako Kajiwara, Kanako Nishikido, Toko Inao, Yutaka Yamamoto. Outcome after the introduction of personalized treatment for axilla in patients with clinically node-negative early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-09.

Abstract PO3-23-07: Evaluation of the role of axillary ultrasound to estimate axillary nodal burden to guide de-escalation of upfront axillary surgery in node positive early breast cancer patients

Abstract Background: Axillary surgery is now routinely de-escalated in clinically node negative breast cancer patients with limited axillary nodal burden (up to 2 involved sentinel nodes) based on the results of ACOSOG-Z0011 and AMAROS trials. However, patients with proven axillary metastasis following on ultrasound (AUS) guided core needle biopsy (CNB), undergoing primary surgery are still subjected to an axillary lymph node dissection (ALND) irrespective of the magnitude of the axillary nodal burden. If we could predict axillary nodal burden with a low false negative rate (FNR) for the presence of extensive axillary nodal involvement, we can then hypothesize that axillary surgery could be safely de-escalated in this cohort of patients. We investigated whether pre-operative AUS suggesting limited axillary burden is sensitive enough to rule out gross axillary disease burden. Methods: A single institution retrospective study. We undertook an electronic chart review of all T1 to T3 patients undergoing upfront ALND with either mastectomy or breast conserving surgery between January 2019 and June 2023. Patients with palpable axillary nodes, locally advanced breast cancer or a completion ALND after positive sentinel lymph node biopsy (SLNB) were excluded from the study. Clinical and pathological characteristics associated with nodal burden of disease were evaluated. Limited axillary burden was defined as < 2 involved nodes with ≥3 taken as gross nodal burden for primary analyses. Sensitivity analyses were carried out with limited axillary burden defined as < 3 involved nodes (N1) and ≥4 (N2) taken as gross nodal burden. Subgroup analyses in T1 or T2 tumors were carried out as well. The probabilities of discordant events, defined as limited burden on AUS-CNB but gross burden on final histopathology evaluation (HPE), assuming 10% FNR, were estimated using inverse cumulative binomial distribution function. Results: Data on the exact number of suspicious nodes on AUS were missing for 2 patients, therefore, the final study cohort included 39 patients. The correlation between AUS nodal burden and that on HPE was moderate (Spearman’s rho = 0.48; p = 0.0018). The sensitivity and specificity of AUS in identifying gross nodal burden were 61% and 81% respectively. Observation of 9 discordant events in 22 patients with low burden on AUS ruled out an FNR of < 10% with 99.99% certainty. The sensitivity and specificity in T1/T2 subgroup were 60% and 75% respectively. The sensitivity analyses classifying N1 as limited and N2 as gross axillary burden showed the sensitivity and specificity of 35% and 82% respectively and an FNR of < 10% was ruled out with 99.996% certainty. Conclusion: Pre-operative AUS alone lacks the sensitivity and specificity to accurately predict the true axillary nodal burden to safely guide de-escalation of axillary surgery. AUS followed by targeted axillary dissection (TAD) in conjunction with a dual technique SLNB may provide the desired sensitivity and specificity to guide de-escalation of axillary surgery. A prospective evaluation of this approach is merited. Given the limited number of patients that could be enrolled in such prospective study from individual institutions, an international collaborative effort is needed to address this important research question. Citation Format: Nidhi Garg, Mangesh Thorat, Hisham Hamed, Ashutosh Kothari. Evaluation of the role of axillary ultrasound to estimate axillary nodal burden to guide de-escalation of upfront axillary surgery in node positive early breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-23-07.

Omission of axillary lymph node dissection for breast cancer patients with three or more positive sentinel lymph nodes.

The ACOSOG Z0011 (Z11) trial assessed the benefit of axillary dissection (ALND) for breast cancer patients with sentinel lymph node (SLN) metastases; however, Z11 excluded patients with ≥ 3 positive SLNs. We analyzed trends in ALND omission in patients with ≥ 3 positive SLNs. Women with ≥ 3 positive SLNs who underwent breast-conserving surgery (BCS) or mastectomy between 2018 and 2020 in the National Cancer Database were included using SLN codes initiated in 2018. Patients with stage IV disease, recurrent breast cancer, and who underwent neoadjuvant chemotherapy were excluded. A multivariable logistic regression model was utilized to determine the proportion who received ALND and factors associated with ALND omission. A subgroup analysis was performed among patients who met the remainder of the Z11 inclusion criteria (BCS, T1/T2 breast cancer). We identified 3654 patients with ≥ 3 positive SLNs. ALND was omitted in 37% of patients, and omission significantly increased from 2018 to 2020 (29% vs. 41%, p < 0.0001). Older age, lower grade tumors, no radiation, non-academic facility, BCS, more SLNs examined and fewer positive SLNs were significantly associated with ALND omission. 942 patients with ≥ 3 positive SLNs met the remainder of the Z11 inclusion criteria. ALND was omitted in 49% of these patients, and omission increased from 2018 to 2020 (44% vs. 49%, p = 0.22). Approximately one-third of patients with ≥ 3 positive SLNs do not undergo ALND; omission of ALND increased from 2018 to 2020. Studies assessing oncologic outcomes of patients with ≥ 3 positive SLNs who do and do not receive ALND are required.

Patterns of completion axillary dissection for patients with cT1-2N0 breast cancer undergoing total mastectomy with positive sentinel lymph nodes.

The ACOSOGZ0011 trial found that overall survival (OS) for patients with 1-2 positive nodes undergoing sentinel lymph node biopsy-alone (SLNB) was noninferior to completion axillary lymph node dissection (ALND), but excluded patients undergoing mastectomy. Our study examined patterns of ALND and its relationship with OS for SLNB-positive patients undergoing mastectomy. The National Cancer Database was queried (2010-2017) for patients with cT1-2N0 breast cancer undergoing mastectomy with positive sentinel lymph nodes. Clinical data were compared. Of 20 001 patients, 11 574 (57.9%) underwent SLNB + ALND, and 8427 (42.1%) had SLNB-alone. The SLNB + ALND group had more positive nodes (mean 2.6 vs. 1.3, p < 0.001) and more frequently received nodal radiation (33.4% vs. 28.9%, p < 0.001). Patients diagnosed in later years were less likely to undergo ALND (2010: reference; 2017:odds ratio: 0.29, 95% confidence interval [CI]:0.25-0.33, p < 0.001). ALND (hazard ratio [HR]: 0.97, 95%CI: 0.89-1.06, p = 0.49) and nodal radiation (HR: 0.92, 95%CI: 0.83-1.02, p = 1.06) were not independently associated with OS. Propensity-score matched 5-year OS was similar (SLNB + ALND: 90.9% vs.SLNB-alone: 90.3%, p = 0.65). For patients undergoing mastectomy for cT1-2N0 breast cancer with positive SLNB, SLNB-alone was common and increased over time. Axillary radiation was not routinely delivered in the SLNB-alone group. Completion ALND and nodal radiation were not associated with improved survival.

Could axillary lymph node dissection be omitted in the mastectomy patient with tumor positive sentinel node?

Recent data from the ACOSOG Z0011 trial suggest that axillary lymph node dissection (ALND) may not be necessary for patients with positive sentinel lymph node biopsy (SLNB) receiving breast-conserving surgery (BCS) with irradiation. However, consensus statements and guidelines have recommended that patients undergoing mastectomy with tumor-positive sentinel node undergo completion ALND. In this study, we compared the locoregional recurrence rate of patients with tumor-positive sentinel nodes among three groups: mastectomy with SLNB, mastectomy with ALND and BCS with SLNB. We identified 6,163 women with invasive breast cancer who underwent surgical resection at our institution between January 2000 and December 2011. Clinicopathologic data obtained from the prospectively collected medical database were analyzed retrospectively. Among the patients with sentinel node positive, mastectomy with SLNB was performed in 39 cases, mastectomy with ALND in 181 cases, and BCS with SLNB in 165 cases. The primary end point was the loco-regional recurrence rate. Clinicopathologic characteristics were similar among the groups. There were no cases of loco-regional recurrence in the sentinel groups. At a median follow-up of 61.0 months (last follow-up May 2013), the loco-regional recurrence rate of each group was 0% for BCS with SLNB and mastectomy with SLNB only, and 1.7% for mastectomy with ALND (p=0.182). In our study, there was no significant difference in loco-regional recurrence rates between groups. This result lends weight to the argument that SLNB without ALND may be a reasonable management for selected patients with appropriate surgery and adjuvant systemic therapy.

Axillary Lymph Node Dissection is Associated with Improved Survival Among Men with Invasive Breast Cancer and Sentinel Node Metastasis.

Male breast cancer (MBC) is rare, and management is extrapolated from trials that enroll only women. It is unclear whether contemporary axillary management based on data from landmark trials in women may also apply to men with breast cancer. This study aimed to compare survival in men with positive sentinel lymph nodes after sentinel lymph node biopsy (SLNB) alone versus complete axillary dissection (ALND). Using the National Cancer Database, men with clinically node-negative, T1 and T2 breast cancer and 1-2 positive sentinel nodes who underwent SLNB or ALND were identified from 2010 to 2020. Both 1:1 propensity score matching and multivariate regression were used to identify patient and disease variables associated with ALND versus SLNB. Survival between ALND and SLNB were compared using Kaplan-Meier methods. A total of 1203 patients were identified: 61.1% underwent SLNB alone and 38.9% underwent ALND. Treatment in academic centers (36.1 vs. 27.7%; p < 0.0001), 2 positive lymph nodes on SLNB (32.9 vs. 17.3%, p < 0.0001) and receipt or recommendation of chemotherapy (66.5 vs. 52.2%, p < 0.0001) were associated with higher likelihood of ALND. After propensity score matching, ALND was associated with superior survival compared with SLNB (5-year overall survival of 83.8 vs. 76.0%; log-rank p = 0.0104). The results of this study suggest that among patients with early-stage MBC with limited sentinel lymph node metastasis, ALND is associated with superior survival compared with SLNB alone. These findings indicate that it may be inappropriate to extrapolate the results of the ACOSOG Z0011 and EORTC AMAROS trials to MBC.

Automated Breast Ultrasound (ABUS)-based radiomics nomogram: an individualized tool for predicting axillary lymph node tumor burden in patients with early breast cancer

ObjectivesPreoperative evaluation of axillary lymph node (ALN) status is an essential part of deciding the appropriate treatment. According to ACOSOG Z0011 trials, the new goal of the ALN status evaluation is tumor burden (low burden, < 3 positive ALNs; high burden, ≥ 3 positive ALNs), instead of metastasis or non-metastasis.We aimed to develop a radiomics nomogram integrating clinicopathologic features, ABUS imaging features and radiomics features from ABUS for predicting ALN tumor burden in early breast cancer.MethodsA total of 310 patients with breast cancer were enrolled. Radiomics score was generated from the ABUS images. Multivariate logistic regression analysis was used to develop the predicting model, we incorporated the radiomics score, ABUS imaging features and clinicopathologic features, and this was presented with a radiomics nomogram. Besides, we separately constructed an ABUS model to analyze the performance of ABUS imaging features in predicting ALN tumor burden. The performance of the models was assessed through discrimination, calibration curve, and decision curve.ResultsThe radiomics score, which consisted of 13 selected features, showed moderate discriminative ability (AUC 0.794 and 0.789 in the training and test sets). The ABUS model, comprising diameter, hyperechoic halo, and retraction phenomenon, showed moderate predictive ability (AUC 0.772 and 0.736 in the training and test sets). The ABUS radiomics nomogram, integrating radiomics score with retraction phenomenon and US-reported ALN status, showed an accurate agreement between ALN tumor burden and pathological verification (AUC 0.876 and 0.851 in the training and test sets). The decision curves showed that ABUS radiomics nomogram was clinically useful and more excellent than US-reported ALN status by experienced radiologists.ConclusionsThe ABUS radiomics nomogram, with non-invasive, individualized and precise assessment, may assist clinicians to determine the optimal treatment strategy and avoid overtreatment.

Abstract P3-05-32: Positive sentinel lymph node does not affect prognosis in T1 breast cancer patients who undergo breast conserving surgery with sentinel lymph node biopsy

Abstract Backgrounds: The ACOSOG Z0011 trial revealed oncologic outcomes in patients who underwent breast conserving surgery (BCS) and sentinel lymph node biopsy only versus completion axillary dissection to be equivalent. It was also reported that axillary recurrence rate to be not different between axillary dissection group and SLNB only group, despite the positive rate of over 20% in non-sentinel lymph nodes. It led to suspicion that the role of SLNB in local control to be less significant than previously recognized. Currently trials such as SOUND trial and NAUTILUS trial are being conducted in cT1N0 breast cancer undergoing BCS to compare the outcomes between the current standard surgery and no axillary surgery. Purposes: This study aimed to investigate the factors associated with positive SLN in patients with T1 breast cancer, including T substages. We also evaluated the oncologic outcomes according to SLN positivity. Method: We retrospectively reviewed medical records of patients with pT1 breast cancer who underwent BCS including SLNB at Seoul National University Bundang Hospital from 2010 to 2015 (n=986). SLN positive was defined as one or more micro- to macro-metastasis in axillary lymph node specimen. Overall, regional, and systemic recurrence-free survival (RFS, RRFS, SRFS) and overall survival (OS) were estimated by the Kaplan-Meier analysis. Result: Of 986 patients, positive SLN was observed in 116 patients (11.8%). Regarding T substages, T1mic, T1a, and T1b gouprs showed SLN positive rate of 0%, 3.4%, and 8.5% respectively whereas T1c showed 15.3%. Multivariable logistic regression analyses revealed clinical T stage (OR 1.791, 95% CI 1.061-3.023, P=0.029), &amp;gt;C2 finding in preoperative axillary ultrasonograpy (OR 3.021, 95% CI 1.740-5.248, P&amp;lt; 0.001), usual histologic type including invasive ductal carcinoma, invasive lobular carcinoma, and metaplastic carcinoma confirmed in preoperative biopsy (OR 4.406, 95% CI 1.357-14.305, P=0.014) to be independent predictive factors for SLN positivity. The median follow-up period was 103.03 months. The 5 year RFS, RRFS, SRFS, and OS showed no statistical difference between SLN positive group and negative group. In multivariable Cox regression analysis, serum CEA level higher than 5ng/ml at diagnosis (HR 7.534, 95% CI 3.336-17.019, P=0.002) and Ki-67 level higher than 20% (HR 7.534, 95% CI 3.336-17.019, P&amp;lt; 0.001) were shown to be the independent prognostic factors for RFS. Conclusion: Our data implicates that patients with T1c breast cancer should undergo SLNB at all times presently, considering substantially higher SLN positive rate compared to other T1 substages (16.8% vs. 6.1%, P&amp;lt; 0.001) although no survival difference was observed between SLN positive group and negative group. Kaplan-Meier curve of recurrence-free survival and overall survival Kaplan-Meier curve of recurrence-free survival and overall survival Kaplan-Meier analyses revealed no difference of recurrence-free survival, overall survival between SLN-positive and SLN-negative group. Univariable and multivariable model for recurrence-free survival Higher Ki-67 expression, ER negativity, PR negativity, HER2 positivity were shown to be independent risk factors associated with shorter RFS. Multivariable analysis showed higher Ki-67 expression as the sole independent risk factor for shorter RFS. Citation Format: Hyoung Won Koh, Hee-Chul Shin, Eun-Kyu Kim, Eunyoung Kang. Positive sentinel lymph node does not affect prognosis in T1 breast cancer patients who undergo breast conserving surgery with sentinel lymph node biopsy. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-32.

Comparison of survival outcomes between axillary conservation and axillary lymph node dissections in N1 early breast cancer: a propensity-matched SEER analysis

BackgroundSentinel lymph node dissection (SLND) is an alternative to axillary lymph node dissection (ALND) for breast cancer surgery. But the criteria of SLND only for patients with limited disease in the sentinel node is disputed.MethodsFrom the Surveillance, Epidemiology, and End Results (SEER) database, 2000–2015, we identified 97,296 early breast cancer females with 1–3 axillary lymph nodes macro-metastasis. Of them, 1–5 (axillary conservation group), 6–9, and ≥ 10 (ALND group) axillary lymph nodes were dissected in 28,639, 16,838, and 51,819 patients, respectively. According to the criteria of the ACOSOG Z0011 trial, two historical cohort studies of patients who underwent lumpectomy or mastectomy were conducted and the survival outcomes between ALND and axillary conservation were compared.ResultsOverall, dissection of 6–9 regional lymph nodes resulted in the worst prognosis. After propensity-matched analysis, it was found that patients in the axillary conservation group had worse survival than the ALND group in overall survival. No significant difference in prognosis between the group undergoing lumpectomy was found both in OS and BCSS. Subgroup analysis revealed that Grade 3, T2, two lymph nodes positive, or Her2 positive were the main causes of worse survival in the axillary conservation group.ConclusionNot all patients with N1 early breast cancer suit axillary conservation. Axillary conservation was sufficient in patients who were treated with lumpectomy. ALND cannot be omitted in patients who were ineligible for the Z0011 and undergoing mastectomy with the following characteristics: T2, Grade 3, two positive lymph nodes, and Her2 positive, which may be better complemented to the Z0011 trial. Hence, under different surgical methods, the clinical precision treatment of ALND or axillary preservation is essential.

77 (PB-077) Poster - Initial experience with targeted axillary dissection (TAD) guided by ultrasound in early-stage node positive breast cancer patients undergoing upfront surgery

Background: Since publication of ACOSOG Z0011 trial, the standard of care of early-stage breast cancer patients with 1–2 positive sentinel lymph nodes (SLN) is to avoid completion of node dissection, assuming the risk of leaving additional positive non-SLN in 27% patients without a detrimental effect on their disease free survival (DFS) or overall survival (OS).

Update on sentinel node pathology in breast cancer

Pathologic examination of the sentinel lymph nodes (SLNs) in patients with breast cancer has been impacted by the publication of practicing changing trials over the last decade. With evidence from the ACOSOG Z0011 trial to suggest that there is no significant benefit to axillary lymph node dissection (ALND) in early-stage breast cancer patients with up to 2 positive SLNs, the rate of ALND, and in turn, intraoperative evaluation of SLNs has significantly decreased. It is of limited clinical significance to pursue multiple levels and cytokeratin immunohistochemistry to detect occult small metastases, such as isolated tumor cells and micrometastases, in this setting. Patients treated with neoadjuvant therapy, who represent a population with more extensive disease and aggressive tumor biology, were not included in Z0011 and similar trials, and thus, the evidence cannot be extrapolated to them. Recent trials have supported the safety and accuracy of sentinel lymph node biopsy (SLNB) in these patients when clinically node negative at the time of surgery. ALND remains the standard of care for any amount of residual disease in the SLNs and intraoperative evaluation of SLNs is still of value for real time surgical decision making. Given the potential prognostic significance of residual small metastases in treated lymph nodes, as well as the decreased false negative rate with the use of cytokeratin immunohistochemistry (IHC), it may be reasonable to maintain a low threshold for the use of cytokeratin IHC in post-neoadjuvant cases. Further recommendations for patients treated with neoadjuvant therapy await outcomes data from ongoing clinical trials. This review will provide an evidence-based discussion of best practices in SLN evaluation.

Is Routine Intraoperative Frozen Section Analysis of Sentinel Lymph Nodes Necessary in Every Early-Stage Breast Cancer?

PurposeClinical application of the ACOSOG Z0011 trial results allows clinically node-negative breast cancer patients who meet criteria to avoid axillary dissection even when 1–2 sentinel lymph nodes (SLNs) are positive for metastatic disease. Intraoperative frozen section (iFS) analyses of SLNs were thought to reduce re-operation rates despite variable reported sensitivity and possibility of a false negative result. This study evaluated the rate of re-operations prevented by SLN iFS in a tertiary care hospital in Bangkok, Thailand, over a 6-year time-frame.Patients and MethodsFrom April 2016 to April 2022, 1284 sentinel lymph node biopsy (SLNB) procedures were performed. Of these, 214 cases were breast-conserving surgery in accordance with the ACOSOG criteria with concomitant usage of iFS. Clinicopathological features of these cases were collected and analyzed. Re-operation rates prevented by the additional intervention were reported.ResultsOnly five additional operations were prevented with the usage of 214 iFS. The discordance rate between frozen and permanent sections in terms of presence of metastatic disease and number of total lymph nodes was around 15%. Tumor staging, node staging, Nottingham histologic grading and lymphovascular invasion are significant predictors of SLN metastasis.ConclusioniFS results in a very low prevention rate for follow-up ALND in patients with preoperative clinically negative axillary nodes and is associated with a non-negligible discordance rate with permanent sections. Our study suggests iFS may be avoided in most cases of early-stage clinically and radiographically node-negative breast cancer patients. Doing so may reduce surgical costs and total operative time without a significant impact on the overall quality of treatment and standard of care.

Impact of the ACOSOG Z0011 trial on surgical practice in Asian patients: trends in axillary surgery for breast cancer from a Korean Breast Cancer Registry analysis

BackgroundSince the publication of the Z0011 trial, practice-changing clinical guidelines for breast surgery have been developed. Although recent studies confirmed the feasibility of the Z0011 strategy in Asian populations, there has been no study on the trends of axillary surgery in Asian cohort. This study aimed to investigate the time trend of axillary surgery for breast cancer from a Korean Breast Cancer Registry to understand the impact of the Z0011 trial in Asian patients.MethodsWe collected prospectively constructed data from the nationwide Korean Breast Cancer Registry (KBCR). We identified patients who underwent sentinel node biopsy followed by breast-conserving surgery from 2011 to 2018 and were found to have pathological stage T1-2N1-3M0 disease. Regression analyses were performed to compare the downward trend of axillary lymph node dissection (ALND) in Korean cohort with that previously reported in a Dutch cohort.ResultsFrom KBCR data, 7478 patients met the inclusion criteria. The proportion of ALND significantly decreased from 2011 (76.6%) to 2018 (47.5%). Multivariate analysis revealed that earlier years at diagnosis, larger tumor size, and lymphatic invasion were associated with a higher odds ratio of performing ALND. Compared to the Dutch cohort, the downward trend of ALND in Korea was significantly more gradual (annual percent change: 37.2 vs. 5.8%, p < 0.001).ConclusionsThis study demonstrated a downward trend of ALND in Korean patients with breast cancer. However, the rate of decrease was significantly slower than that in the Dutch cohort.

Observational study of axilla treatment for breast cancer patients with 1 to 3 positive micrometastases or macrometastases in sentinel lymph nodes.

e12576 Background: From the results of ACOSOG Z0011, IBCSG23-01 and AMAROS trials, axilla surgery in node-positive breast cancer (BC) tends to be less invasive with sentinel node biopsy (SNB) followed by adjuvant therapy and regional node irradiation (RNI). However, optimized axilla treatment including SNB without RNI is still debated. The Japanese Society for Sentinel Node Navigation Surgery conducted a multi-institutional prospective cohort study to compare SNB with SNB followed by axillary lymph node dissection (ALND) in cases with positive-sentinel lymph nodes (SLN)(UMIN No. 000011782, Jpn J Clin Oncol, p.876-9, 2014). Methods: Female BC patients with cT1-3N0-1M0 were eligible. When 1 to 3 positive micrometastases or macrometastases in SLN were confirmed by histological or molecular diagnosis, SNB alone or additional ALND had been decided by physician’s discretion. Primary chemotherapy before or after SNB was acceptable for registration. Lymph node sampling was also allowed in the SNB group. Cases with bilateral BC, isolated tumor cells only in SLN, past history of invasive cancer within 5 years at the registration were ineligible. The primary endpoint was the 5-year recurrence rate of regional node (RN) in the SNB group. The secondary endpoint was overall survival (OS). We planned to collect 240 patients to reject that the 5-year recurrence rate of RN was more than 10% assuming the rate 5%. To compare the SNB group and ALND group, the propensity score matching (PSM) was performed. Matching variables were initial treatment, metastatic size and numbers of SLN, clinical stage, age, body mass index, menopausal status, family history, past history of invasive cancer, breast surgery. Results: Eight-hundred eighty cases had been registered between 2013 and 2016. In the 871 eligible cases, 308 cases were the SNB group. At the median follow-up of 6.3 years, 5-year recurrence rate of RN was 2.7% [95% confidence interval, 1.4% to 5.4%] and 5-year OS was 97.6% [94.9% to 98.8%]. After PSM, 209 cases were matched in the SNB and ALND group. Among them, 343 cases (82%) received operation at initial treatment. Partial and total mastectomy was performed in 225 (54%) and 193 cases (46%), respectively. One-positive SLN was recorded in 366 cases (88%), 2 in 48 (11%) and 3 in 4 (1%). Macrometastases and micrometastases in SLN were diagnosed in 271 (65%) and 147 cases (35%), respectively. Three-hundred seventy-six cases (90%) belonged to luminal-like subtype. RNI was underwent in 42 cases (20%) of the SNB group and 13 cases (6%) of the ALND group. Five-year recurrence rate of RN was 2.1% [0.8% to 5.5%] and 2.0% [0.8% to 5.3%] for the SNB and ALND group, respectively. Conclusions: Our series suggests that RNI is not necessary for regional control in cases with 1 to 3 positive SLN. In conclusion, SNB alone is acceptable in cases with fewer metastatic SLN. Clinical trial information: UMIN No. 000011782.

No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS]: protocol of a prospective randomized clinical trial

BackgroundFollowing sentinel lymph node biopsy (SLNB), the axillary recurrence rate is very low although SLNB has a false-negative rate of 5–10%. In the ACOSOG Z0011 trial, non-sentinel positive-lymph nodes were found in more than 20% of the axillary dissection group; the SLNB only group did not have a higher axillary recurrence rate. These findings raised questions about the direct therapeutic effect of the SLNB. SLNB has post-surgical complications including lymphedema. Considering advances in imaging modalities and adjuvant therapies, the role of SLNB in early breast cancer needs to be re-evaluated.MethodsThe NAUTILUS trial is a prospective multicenter randomized controlled trial involving clinical stage T1–2 and N0 breast cancer patients receiving breast-conserving surgery. Axillary ultrasound is mandatory before surgery with predefined imaging criteria for inclusion. Ultrasound-guided core needle biopsy or needle aspiration of a suspicious node is allowed. Patients will be randomized (1:1) into the no-SLNB (test) and SLNB (control) groups. A total of 1734 patients are needed, considering a 5% non-inferiority margin, 5% significance level, 80% statistical power, and 10% dropout rate. All patients in the two groups will receive ipsilateral whole-breast radiation according to a predefined protocol. The primary endpoint of this trial is the 5-year invasive disease-free survival. The secondary endpoints are overall survival, distant metastasis-free survival, axillary recurrence rate, and quality of life of the patients.DiscussionThis trial will provide important evidence on the oncological safety of the omission of SLNB for early breast cancer patients undergoing breast-conserving surgery and receiving whole-breast radiation, especially when the axillary lymph node is not suspicious during preoperative axillary ultrasound.Trial registrationClinicalTrials.gov, NCT04303715. Registered on March 11, 2020.

Abstract OT1-04-02: The NAUTILUS trial (No Axillary sUrgical Treatment In clinically Lymph node negative patients after UltraSonography): A prospective multicenter randomized phase III trial (NCT04303715)

Abstract Background. Sentinel lymph node biopsy (SLNB) is currently the standard axillary staging procedure for clinically node-negative breast cancer. According to the ACOSOG Z0011 trial, axillary lymph node dissection (ALND) is now often omitted for clinically node-negative cT1-2 breast cancer patients undergoing breast-conserving surgery even if 1 or 2 metastatic lymph nodes (LN) are identified. It was shown that radiotherapy contributes to regional control of the axilla non-inferior to ALND even in the presence of metastatic LNs. Furthermore, LN metastasis has a limited role in planning adjuvant systemic therapy for hormone receptor-negative breast cancers, and also for hormone receptor-positive, HER2-negative breast cancer with increased use of genomic assays. SLNB is not without complications and omitting axillary staging operation could improve quality of life. Trial Design. In this multicenter, phase III randomized controlled trial including 9 study sites in South Korea, we plan to 1:1 randomize 1734 patients to either omit SLNB (Arm 1) or receive SLNB (Arm 2). Additional ALND can be performed according to the discretion of the surgeon according to the SLNB results. All patients must receive whole-breast irradiation ± tumor bed boost. The recommended upper margin of the radiation field is within 2cm of the humeral head. ClinicalTrials.gov identifier: NCT04303715. Eligibility. Inclusion criteria: women ≥19 years; cT1-2N0M0 unilateral invasive breast carcinoma; all molecular subtypes; clinically and radiologically tumor size ≤ 5cm; clinically- and ultrasonogram-negative axillary lymph nodes, or no tumor on core needle biopsy or fine needle aspiration cytology in case of suspicious lymph nodes; candidate for breast-conserving surgery with no restriction to radiotherapy and adequate systemic therapy. Exclusion criteria: history of any malignancy within 5 years (exception: thyroid cancer and well-treated skin cancer except melanoma); bilateral breast cancer; neoadjuvant chemotherapy; candidate for total mastectomy; male breast cancer. Specific Aims. Primary objective is to test the hypothesis that omitting SLNB for breast cancer is non-inferior to axillary staging operation in terms of 5-year disease-free survival. Secondary objectives are to compare overall survival, distant metastasis-free survival, locoregional recurrence, quality of life assessment, and DFS and axillary recurrence according to molecular subtypes. Statistical Methods. With an expected 5-year DFS of 86% for Arm 2, Arm 1(SLNB omission) will be assessed with a non-inferiority limit of 5% and hazard ratio of 1.4, power 80%, and significance level of 5%, where 224 events are required. The calculated sample size is 780 per study arm, resulting in a total of 1,734 patients assuming a 10% drop-out rate. Present Accrual and Target Accrual. The first patient was randomized on September 15, 2020. As of July 9, 2021, 480 patients have been randomized. Target accrual of 1734 patients is expected to be complete by April 2023, with the primary endpoint analysis expected in 2028. Citation Format: Han-Byoel Lee, Ji Gwang Jung, Jung Min Chang, Ji Hyun Chang, Woo Kyung Moon, Kyung Hwan Shin, Il Yong Chung, Seok Jin Nam, Eun-Kyu Kim, Seeyoun Lee, Seho Park, Woo Sung Lim, Yongsik Jung, Wonshik Han. The NAUTILUS trial (No Axillary sUrgical Treatment In clinically Lymph node negative patients after UltraSonography): A prospective multicenter randomized phase III trial (NCT04303715) [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 OT1-04-02.

Preliminary results of the MUltimodal TArgeted axillary Surgery (MUTAS) study (ClinicalTrials.gov: NCT04039893): tailoring axillary dissection in breast cancer patients with infiltrated lymph nodes.

Background: The surgical management of breast cancer patients with infiltrated axillary lymph nodes (ALNs) at diagnosis is controversial, as some centres perform upfront axillary dissection (AD) while other centres perform the sentinel node (SN) mapping, so that some patients may benefit from the ACOSOG Z0011 trial criteria to skip further surgery. The primary aim of the MUTAS trial is to establish if performing the SN in breast cancer patients with confirmed infiltrated ALNs could be useful to tailor axillary surgery.

Choice of Mastectomy May Increase the Extent of Axillary Surgery in Women with Breast Cancer

Based on the ACOSOG Z0011 trial, women who undergo breast conservation therapy (BCT) and have limited disease in the axilla on sentinel lymph node (SLN) biopsy do not require axillary lymph node dissection (ALND). In this study we investigate the incidence of ALND in patients undergoing elective mastectomy with limited disease in the axilla to identify how many women may have been spared additional axillary surgery if they chose BCT. All women with invasive breast cancer treated at a single tertiary care breast center from 2010-2018 who were candidates for BCT but elected mastectomy and underwent SLN biopsy were identified through retrospective review of a prospectively maintained database. The primary outcome of interest was the incidence of ALND in women found to have a limited burden of disease in the axilla (1-2 positive SLNs). The study population comprised 151 patients with invasive breast cancer eligible for BCT who chose mastectomy. On final pathology, 34 patients had 1-2 positive SLNs, and 16 of these patients underwent completion ALND. These 16 patients out of 151 overall lumpectomy candidates electing mastectomy (10.6%) could have been spared ALND if they did not elect mastectomy. BCT candidates electing mastectomy have a 10.6% chance of undergoing more extensive axillary surgery than would have been recommended with BCT alone. The increased risk of undergoing additional axillary surgery should be incorporated into the preoperative discussion for patients choosing between BCT and mastectomy.