Lymphedema Rates Following Axillary Lymph Node Dissection With and Without Immediate Lymphatic Reconstruction: A Prospective Trial.

BACKGROUND: Immediate lymphatic reconstruction (ILR) has been proposed to decrease lymphedema rates. The primary aim of our study was to determine whether ILR decreased the incidence of lymphedema in patients undergoing axillary lymph node dissection (ALND). METHODS: We conducted a two-site pragmatic study of ALND with or without ILR, employing surgeon-level cohort assignment, based on breast surgeons' preferred standard practice. Lymphedema was assessed by limb volume measurements, patient self-reporting, provider documentation, and International Classification of Diseases, Tenth Revision (ICD-10) codes. RESULTS: Overall, 230 patients with breast cancer were enrolled; on an intention-to-treat basis, 99 underwent ALND and 131 underwent ALND with ILR. Of the 131 patients preoperatively planned for ILR, 115 (87.8%) underwent ILR; 72 (62.6%) were performed by one breast surgical oncologist and 43 (37.4%) by fellowship-trained microvascular plastic surgeons. ILR was associated with an increased risk of lymphedema when defined as ≥10% limb volume change on univariable analysis, but not on multivariable analysis, after propensity score adjustment. We did not find a statistically significant difference in limb volume measurements between the two cohorts when including subclinical lymphedema (≥5% inter-limb volume change), nor did we see a difference in grade between the two cohorts on an intent-to-treat or treatment received basis. For all patients, considering ascertainment strategies of patient self-reporting, provider documentation, and ICD-10 codes, as a single binary outcome measure, there was no significant difference in lymphedema rates between those undergoing ILR or not. CONCLUSION: We found no significant difference in lymphedema rates between patients undergoing ALND with or without ILR.

Internal Mammary Lymphadenopathy Does Not Impact Oncologic Outcomes in Patients Treated with Neoadjuvant Chemotherapy: Results from the I-SPY2 Clinical Trial.

BACKGROUND: Internal mammary lymphadenopathy (IML) plays a role in breast cancer stage and prognosis. We aimed to evaluate method of IML detection, how IML impacts response to neoadjuvant chemotherapy (NAC), and oncologic outcomes. METHODS: We evaluated patients enrolled in the I-SPY-2 clinical trial from 2010 to 2022. We captured the radiographic method of IML detection (magnetic resonance imaging [MRI], positron emission tomography/computed tomography [PET/CT], or both) and compared patients with IML with those without. Rates of locoregional recurrence (LRR), distant recurrence (DR) and event-free survival (EFS) were compared by bivariate analysis. RESULTS: Of 2095 patients, 198 (9.5%) had IML reported on pretreatment imaging. The method of IML detection was 154 (77.8%) MRI only, 11 (5.6%) PET/CT only, and 33 (16.7%) both. Factors associated with IML were younger age (p = 0.001), larger tumors (p < 0.001), and higher tumor grade (p = 0.027). Pathologic complete response (pCR) was slightly higher in the IML group (41.4% vs. 34.0%; p = 0.03). There was no difference in breast or axillary surgery (p = 0.41 and p = 0.16), however IML patients were more likely to undergo radiation (68.2% vs. 54.1%; p < 0.001). With a median follow up of 3.72 years (range 0.4-10.2), there was no difference between IM+ versus IM- in LRR (5.6% vs. 3.8%; p = 0.25), DR (9.1% vs. 7.9%; p = 0.58), or EFS (61.6% vs. 57.2%; p = 0.48). This was true for patients with and without pCR. CONCLUSIONS: In this large cohort of patients treated with NAC, outcomes were not negatively impacted by IML. We demonstrated that IML influences treatment selection but is not a poor prognostic indicator when treated with modern NAC and multidisciplinary disease management.

Clipping the Positive Lymph Node in Patients with Clinically Node Positive Breast Cancer Treated with Neoadjuvant Chemotherapy: Impact on Axillary Surgery in the ISPY-2 Clinical Trial.

BACKGROUND: For patients with clinically node-positive (cN+) breast cancer undergoing neoadjuvant chemotherapy (NAC), retrieving previously clipped, biopsy-proven positive lymph nodes during sentinel lymph node biopsy [i.e., targeted axillary dissection (TAD)] may reduce false negative rates. However, the overall utilization and impact of clipping positive nodes remains uncertain. PATIENTS AND METHODS: We retrospectively analyzed cN+ ISPY-2 patients (2011-2022) undergoing axillary surgery after NAC. We evaluated trends in node clipping and associations with type of axillary surgery [sentinel lymph node (SLN) only, SLN and axillary lymph node dissection (ALND), or ALND only] and event-free survival (EFS) in patients that were cN+ on a NAC trial. RESULTS: Among 801 cN+ patients, 161 (20.1%) had pre-NAC clip placement in the positive node. The proportion of patients that were cN+ undergoing clip placement increased from 2.4 to 36.2% between 2011 and 2021. Multivariable logistic regression showed nodal clipping was independently associated with higher odds of SLN-only surgery [odds ratio (OR) 4.3, 95% confidence interval (CI) 2.8-6.8, p < 0.001]. This was also true among patients with residual pathologically node-positive (pN+) disease. Completion ALND rate did not differ based on clip retrieval success. No significant differences in EFS were observed in those with or without clip placement, both with or without successful clip retrieval [hazard ratio (HR) 0.85, 95% CI 0.4-1.7, p = 0.7; HR 1.8, 95% CI 0.5-6.0, p = 0.3, respectively]. CONCLUSION: Clip placement in the positive lymph node before NAC is increasingly common. The significant association between clip placement and omission of axillary dissection, even among patients with pN+ disease, suggests a paradigm shift toward TAD as a definitive surgical management strategy in patients with pN+ disease after NAC.

Breast Conservation Surgery and Mastectomy Have Similar Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From 1462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8-4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Lymph Node Positivity of Axillary Reverse Mapping Lymph Nodes at the Time of Axillary Lymph Node Dissection: Two-Site Prospective Trial.

BACKGROUND: Axillary reverse mapping (ARM) was introduced in 2007 to identify and selectively preserve upper-extremity lymphatics during axillary lymph node surgery to decrease the risk of lymphedema. The patient population in which an ARM lymph node (LN) can be preserved during an axillary lymph node dissection (ALND) has not been established to date. This study aimed to determine the frequency of metastatic involvement of an ARM LN among patients undergoing ALND. METHODS: Patients undergoing ALND with or without immediate lymphatic reconstruction (ILR) were enrolled in a prospective trial at two institutional sites between April 2018 and Decemeber 2022. This report analyzes the ARM node positivity and total LN positivity rates during ALND for the cohort of patients enrolled in the ILR intervention arm of the study. RESULTS: The inclusion criteria were met by 139 patients, who made up the study population (133 with breast cancer and 6 with other disease). Of the breast cancer patients, 99.2% were female, 35.3% (47/133) were cT3 or greater, and 96.2% (128/133) had cN1 or greater disease. For 55 of the 133 patients (41.4%), the ARM nodes were marked and specified in the pathology report. Of the 55 patients, 39 (70.9%) had a positive LN at ALND. Of these 55 patients, 11 (20%) had positive ARM nodes. The ARM LN was the only positive node in 3 of the 11 patients. CONCLUSION: In the contemporary patient population undergoing ALND, the positivity rate of the ARM LN was relatively high, suggesting that leaving ARM LNs in patients undergoing ALND may not be oncologically safe.

Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Factors Associated With Ultrasound Color Doppler Twinkling by Breast Biopsy Markers: In Vitro and Ex Vivo Evaluation of 35 Commercially Available Markers.

BACKGROUND. Targeted axillary lymph node dissection after neoadjuvant systemic therapy (NST) for breast cancer depends on identifying marked metastatic lymph nodes. However, ultrasound visualization of biopsy markers is challenging. OBJECTIVE. The purpose of our study was to identify biopsy markers that show actionable twinkling in cadaveric breast and to assess the association of actionable twinkling with markers' surface roughness. METHODS. Commercial breast biopsy markers were evaluated for twinkling artifact in various experimental conditions relating to scanning medium (solid gel phantom, ultrasound coupling gel, cadaveric breast), transducer (ML6-15, 9L, C1-6), and embedding material (present vs absent). Markers were assigned twinkling scores from 0 (confident in no twinkling) to 4 (confident in exuberant twinkling); a score of 3 or greater represented actionable twinkling (sufficient confidence to rely solely on twinkling for target localization). Markers were hierarchically advanced to evaluation with increasingly complex media if showing at least minimal twinkling for a given medium. A 3D coherence optical profiler measured marker surface roughness. Mixed-effects proportional odds regression models assessed associations between twinkling scores and transducer and embedding material; Wilcoxon rank sum test evaluated associations between actionable twinkling and surface roughness. RESULTS. Thirty-five markers (21 with embedding material) were evaluated. Ten markers without embedding material advanced to evaluation in cadaveric breast. Higher twinkling scores were associated with presence of embedding material (odds ratio [OR] = 5.05 in solid gel phantom, 9.84 in coupling gel) and transducer (using the C1-6 transducer as reference; 9L transducer: OR = 0.36, 0.83, and 0.04 in solid gel phantom, ultrasound coupling gel, and cadaveric breast; ML6-15 transducer: OR = 0.07, 0.18, and 0.00 respectively; post hoc p between 9L and ML6-15: p < .001, p = .02, and p = .04). In cadaveric breast, three markers (Cork, Professional Q, MRI [Flex]) exhibited actionable twinkling for two or more transducers; surface roughness was significantly higher for markers with than without actionable twinkling for C1-6 (median values: 0.97 vs 0.35, p = .02) and 9L (1.75 vs 0.36; p = .002) transducers. CONCLUSION. Certain breast biopsy markers exhibited actionable twinkling in cadaveric breast. Twinkling was observed with greater confidence for the C1-6 and 9L transducers than the ML6-15 transducer. Actionable twinkling was associated with higher marker surface roughness. CLINICAL IMPACT. Use of twinkling for marker detection could impact preoperative or intraoperative localization after NST.

Overuse of Axillary Surgery in Patients with Ductal Carcinoma In Situ: Opportunity for De-escalation.

BACKGROUND: Ductal carcinoma in situ (DCIS) is noninvasive breast cancer and therefore nodal staging is not routinely recommended. We evaluated the use of and factors associated with axillary surgery in DCIS in the National Cancer Database (NCDB). METHODS: DCIS cases were identified from the NCDB 2012-2018. Use of axillary surgery was evaluated over time, and factors associated with axillary surgery were assessed for breast-conserving surgery (BCS) and mastectomy groups. RESULTS: We identified 178,762 patients, median age of 60 years. Majority of DCIS (87%) was ER-positive, and 14% low, 43% intermediate, and 44% high grade. Median DCIS size was 1.1 cm. BCS was performed in 72%, whereas 28% had mastectomy. Overall axillary surgery was performed in 38% and was higher in patients undergoing mastectomy compared with patients undergoing BCS (88% vs. 19%, p < 0.001). At axillary surgery, the vast majority (92%) had 1-5 nodes examined, whereas 8% had >5 nodes examined. Over time, axillary surgery decreased in BCS patients (21% in 2012 to 17% in 2018, p < 0.001) but increased slightly in mastectomy patients (86% in 2012 to 90% in 2018, p < 0.001). On multivariable analysis, factors significantly associated with axillary surgery were younger patient age, larger tumor size, higher grade, and ER-negative status. CONCLUSIONS: Factors associated with axillary surgery reflect higher risk disease for upstage to invasive cancer, indicating surgeon judgment. However, despite axillary surgery being overtreatment of DCIS, it is common in mastectomy and is performed for one in five patients undergoing BCS. This provides opportunity for improvement in breast cancer care delivery.

Surgeon Assessment of the Technical Impact of Neoadjuvant Systemic Therapy on Operable Stage III Melanoma.

INTRODUCTION: The effect of neoadjuvant systemic therapies (NST) on technical aspects of operation for resectable stage III melanoma is unknown. Prospective capture of the estimated and actual degree of difficulty of therapeutic lymphadenectomy at presentation and after NST may inform the relative merits of NST versus surgery followed by adjuvant therapy. METHODS: We designed surgeon survey tools to capture key impressions at baseline prior to NST and postoperatively. We conducted a sub-study within a multi-institutional clinical trial for high-risk operable stage III melanoma (NeoACTIVATE, NCT03554083) which enrolls clinically node-positive patients to 12 weeks of combinatorial NST determined by BRAF status. Survey data were analyzed. RESULTS: Surveys were completed for 24 of 25 patients (96%). Affected nodal basins were cervical (3, 13%) axillary (9, 38%), inguinal ± pelvic (14, 58%); 2 (8%) involved ≥ 2 basins. Baseline estimates included largest affected node size (median/range 4/1.4-11 cm), number of involved nodes (median/range 3/1-10) and tumor fixation (present in 12, 50%). At operation, actual degree of difficulty increased from the baseline estimate in 4 (17%) and decreased in 6 (25%). Surgery was less difficult, average, or more difficult versus usual operation in 4, 9, and 11 cases (17%, 38%, 46%), respectively. CONCLUSIONS: Although many operations were judged to be more difficult than the usual therapeutic lymphadenectomy, operation following NST was more often perceived as easier than more difficult versus baseline impression. Engaging surgical oncologists to perform similar structured assessments across clinical trials will permit cross-study analysis of the effect of NSTs on the technical conduct of lymphadenectomy.

Use of the Twelve-Gene Recurrence Score for Ductal Carcinoma in Situ and Its Influence on Receipt of Adjuvant Radiation and Hormonal Therapy.

BACKGROUND: Tumor genomic prognostic assays estimate 10-year local recurrence risk in ductal carcinoma in situ (DCIS) and can guide treatment decisions. This study aimed to evaluate which DCIS patients treated with breast-conserving surgery (BCS) underwent DCIS score genomic testing and the influence of the results on adjuvant treatment recommendations. METHODS: The study identified patients from the National Cancer Database (NCDB) who had DCIS treated with BCS from 2010 to 2016. RESULTS: Of 141,047 patients, 4255 (3%) had a DCIS score assessed, 0.3% in 2010 increasing to 5.8% in 2016 (p < 0.001). The patients most likely to undergo DCIS score assessment had more favorable tumor features in the multivariable analysis. The DCIS score result was documented for 91.4% of the tested patients (n = 3888): 70.5% of the low-risk, 14.9% of the intermediate-risk, and 14.6% of the high-risk patients. The patients with low-risk scores were less likely to have radiation than those with intermediate- or high-risk scores among the patients with either ER + (35.0% vs 71.0% or 81.1%) or ER- disease (48.1% vs 77.0% or 85.5%) (each p ≤ 0.001). The patients who had ER + disease with high- and intermediate-risk scores were most commonly treated with both radiation and hormone therapy (HT) (57.1% and 52.2%), whereas the most common treatment for those with a low-risk DCIS score was HT alone without radiation (37.1%). Comparison of genomic testing with clinicopathologic features showed an independent influence of genomic testing on treatment. CONCLUSIONS: Use of the DCIS score increased over time, predominantly for favorable DCIS. Patients with a low-risk score were significantly less likely to receive radiation, supporting an impact of the DCIS score on treatment de-escalation.

Oncologic Outcomes of Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy for Node-Positive Breast Cancer.

BACKGROUND: Sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy (NAC) has been well studied. However, outcomes data addressing the oncologic safety of this technique are sparse. This study aimed to evaluate use of SLN surgery versus axillary lymph node dissection (ALND) for clinically node-positive patients treated with NAC and to report outcomes. METHODS: The study identified patients at the authors' institution with biopsy proven clinically node-positive (cN1-cN3) breast cancer undergoing axillary surgery after NAC from 2009 to 2019. Practice patterns and outcomes were evaluated. RESULTS: Of 602 patients, 52.3% underwent SLN surgery. Use of SLN surgery increased significantly over time, reaching 75.3% during 2015-2019. For 52.5% of the patients who had an SLN identified, ALND was not used. Use of ALND (± SLN surgery) decreased from 100% in 2009 to 57.2% in 2015-2019. The nodal positivity rate of patients who proceeded directly to ALND was 64.5% (185/287), increasing significantly over time. Factors significantly associated with performing SLN surgery on multivariable analysis were lower presenting clinical T category, lower presenting clinical N category (cN1 vs cN2-3) and HER2-positive status. During the median 34-month follow-up period, 17 regional recurrences were observed (16/443 with ALND; 1/159 with SLN surgery alone), for a 2-year freedom-from-regional-recurrence rate of 99.1% among the SLN surgery patients and 96.4% among the ALND patients (p = 0.10). CONCLUSIONS: For cN1-3 breast cancer treated with NAC, SLN surgery has been incorporated into clinical practice at the authors' institution. In this study, selection for SLN surgery was based on clinical factors and tumor biology. More than half of the patients who were selected for SLN surgery were spared ALND, with a low nodal failure rate and no recurrence-free survival disadvantage at 2 years.

Performance and Clinical Utility of Models Predicting Eradication of Nodal Disease in Patients with Clinically Node-Positive Breast Cancer Treated with Neoadjuvant Chemotherapy by Tumor Biology.

INTRODUCTION: Prediction models are useful to guide decision making. Our goal was to compare three published nomograms predicting axillary response to neoadjuvant chemotherapy (NAC), clinically node-positive breast cancer. METHODS: Patients with cT1-T4, cN1-N3 breast cancer treated with NAC and surgery from 2008 to 2019 were reviewed. The predicted probability of pathologic node-negative (ypN0) status was estimated for each nomogram. Area under the curve (AUC) was compared across models, overall and by biologic subtype. RESULTS: Of 581 patients, 253 (43.5%) were ypN0. ypN0 status varied by subtype: 23.9% for estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), 68.9% for HER2-positive (HER2+), and 47.2% for ER-negative (ER-)/HER2-. The three nomograms had similar AUC values (0.761-0.769; p = 0.80). The Mayo model-predicted probability was significantly lower (p < 0.001) than the observed probability of ypN0 status, while the MD Anderson Cancer Center (MDACC) 1- and 2-predicted probabilities were similar to the observed probability. At a predicted probability threshold of 50%, the Mayo model had the highest sensitivity (89.6%) for detecting ypN+ patients compared with MDACC models 1 and 2 (76.5%; p < 0.001). However, both MDACC models had higher specificity in identifying ypN0 status among HER2+ (81.7%) and ER-/HER2- (75.9-77.6%) patients compared with the Mayo model (59.5% and 43.1%; each p < 0.001). None of the models identified the ER+/HER2- patients with ypN0 status well at the ≥ 50% threshold (specificity 0-9.4%). CONCLUSION: All three models predicting nodal response to NAC performed well overall with respect to discrimination, but differed with respect to calibration and performance at a 50% probability threshold. However, none of the models performed well at the 50% threshold for ER+/HER2- patients.