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Background Chronic inflammatory responses initiated by lymphatic injury play a key role in the pathophysiology of secondary lymphedema. However, it is unclear if baseline inflammation or ethnic/racial variability in inflammatory responses increase lymphedema risk. Crown-like structures of the breast (CLS-B), consisting of macrophages engulfing necrotic adipocytes, are a marker of systemic inflammation and have been implicated in the pathogenesis of breast cancer, but their role in lymphedema development is unknown. Here we determine whether baseline differences in inflammation, characterized by the presence of CLS-B, contributed to lymphedema risk in a diverse cohort of patients treated with ALND. Methods Patients ≥ 18 years undergoing ALND were enrolled in a prospective lymphedema screening study. Body mass index (BMI) and volumetric arm measurements (perometer) were performed at baseline, postoperatively, and every 6 months. Breast tissue obtained at definitive surgery was assessed for CLS-B with CD-68 IHC stain in non-tumor breast tissue. Inflammation severity was determined by number of CLS-B/cm2, with the median used to differentiate between mild and severe inflammation. Lymphedema was defined as a relative arm volume change of ≥10%. Lymphedema incidence was assessed using competing risk analysis and compared between patients with and without CLS-B. Uni- and multivariable analysis was performed to identify factors associated with lymphedema development. Results Between 11/2016-03/2020, 304 ALND patients were enrolled; 281 had at least 6 months of follow-up and were included in the study. Eleven percent self-identified as Asian, 20% Black, 6% Hispanic, and 60% White. Median age was 48 years; median BMI was 26.3 kg/m2, with higher BMI observed in Black and Hispanic women compared to Asian and White women (p < 0.001). Overall, 54% had CLS-B, with severe inflammation (> 0.4 CLS-B/cm2) identified in 71 (25%) patients. CLS-B presence correlated with BMI (36% [BMI < 25], 63% [BMI 25-30], 70% [BMI > 30], p < 0.001) and varied across racial/ethnic groups, with a higher prevalence in Black and Hispanic women (68% [Black], 69% [Hispanic] vs 59% [Asian], 46% [White], p = 0.03) (Table). Inflammation severity did not differ by race/ethnicity (p = 0.11). At 2.1 years median follow-up (IQR 1.6-3.1), 66 women developed lymphedema, with a 2-year lymphedema rate of 21.3% (95% CI 16.4-26.8). Lymphedema incidence was higher among Black and Hispanic women, compared to Asian and White women (2-year rate: 33.8% [Black], 31% [Hispanic], 17.4% [Asian], 18.2% [White], p = 0.002), and was higher among women with CLS-B (2-year rate: 28.2% [CLS-B] vs 12.9% [no CLS-B], p = 0.02). On multivariable analysis, Black race (White [referent]: HR 2.85, 95% CI 1.4-5.8; p = 0.03), receipt of NAC (upfront surgery [referent]: HR 2.46, 95% CI 1.04-5.8, p = 0.04) and older age (HR 1.03, 95% CI 1.01-1.06 per 1-year increase; p = 0.009) were independently associated with lymphedema development, while CLS-B was not (HR 1.37, 95% CI 0.81-2.34, p = 0.2). Conclusions In a prospective cohort of patients treated with ALND, Black race, receipt of NAC, and increasing age, but not CLS-B, were independently associated with lymphedema risk. However, the higher CLS-B prevalence in Black women suggests that they may have a propensity for increased inflammation, which may in part be contributing to the higher lymphedema risk observed, but is likely not the only inflammatory mechanism that modulates risk. Table. Clinical characteristics of study cohort stratified by the presence of CLS-B Citation Format: Andrea V. Barrio, Giacomo Montagna, Varadan Sevilimedu, Ethan Gomez, Dilip Giri, Babak Mehrara, Monica Morrow. Does Breast Inflammation Contribute to Lymphedema Risk in Patients Treated with Axillary Lymph Node Dissection? [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 P5-08-09.

Background: Data on the oncologic safety of omission of axillary lymph node dissection (ALND) in node positive (N+) patients who downstage to ypN0 with neoadjuvant chemotherapy (NAC) is sparse. Additionally, there is no consensus on which axillary staging procedure should be used in this setting, sentinel lymph node biopsy (SLNB) alone or in combination with localization and retrieval of the clipped positive node, also known as targeted axillary dissection (TAD). Whether the reduction in the false negative rate observed with TAD translates into a significant reduction in the rate of axillary recurrence is unknown. We sought to evaluate oncologic outcomes after omission of ALND in a large, real-world cohort of breast cancer (BC) patients and to compare rates of axillary recurrence after SLNB with dual tracer mapping vs. TAD. Methods: Data were collected from 19 centers in the Oncoplastic Breast Consortium (OPBC) and EUBREAST networks. Patients with T1-4 biopsy-proven N1-3 BC who underwent NAC followed by axillary staging with either SLNB with dual tracer mapping or TAD and who were pathologically node negative (ypN0) were included. ypN0 was defined as the absence of any tumor or isolated tumor cells. Competing risk analysis was performed to assess the cumulative incidence rates of axillary recurrence, locoregional recurrence, and any invasive (locoregional or distant) recurrence. Two-year cumulative incidence rates were compared between TAD and SLNB using the Gray’s test. Type I error rate was set to 0.05 (α). Results: We included 785 patients (565 treated with SLNB and 220 with TAD) treated with NAC followed by surgery from 01/2014-12/2020. Median patient age was 50 years. The majority (57%) of patients had clinical T2 tumors, and 95% had N1 disease. Most (55%) were HER2+, and 21% were triple negative. Most patients (81%) received anthracycline and taxane-based chemotherapy regimens, but NAC regimens differed between patients treated with TAD and those treated with SLNB (Table 1). All patients with HER2+ tumors received anti HER2 therapy. Nodal radiotherapy was administered to 76% of patients, and was more common in patients who underwent TAD (82% TAD vs 74% SLNB, p=0.017). Breast pathologic complete response (ypT0/is) was more frequent among those patients that had TAD (80% TAD vs. 66% SLNB, p< 0.001). TAD localization was with wire in 46%, radioactive seed in 40%, ultrasound in 5%, tattoo in 2%, and with a combination of these techniques in 7%. The clipped node was successfully retrieved in 94% of TAD cases. The median number of lymph nodes removed was lower in the TAD group compared to the SLNB group [3 (IQR 3-5) vs 4 IQR 3-5), p< 0.001], as was the median number of sentinel lymph nodes [3 (IQR 2-4) vs 4 IQR 3-5), p< 0.001] (Table 1). The 5-year rates of any axillary recurrence, locoregional recurrence, and any invasive recurrence in the entire cohort were 1.1% (95%CI 0.39-2.4%), 3.1% (95%CI 1.6-5.3%) and 10% (95%CI 7.6-13%), respectively. The two-year cumulative incidence of axillary recurrence did not differ between patients treated with TAD compared to SLNB (0% vs 0.9%, p=0.19). Conclusion: Early axillary recurrence after omission of ALND in patients who successfully downstage from N+ to ypN0 with NAC is a rare event following both SLNB or TAD, and was not significantly lower in TAD than SLNB. Although longer follow-up is needed to confirm these findings, the main advantage of TAD seems to be a reduction in the number of lymph nodes removed. Overall, these results support omission of ALND in patients who successfully downstage to node negative disease after NAC. Table 1: Clinicopathological Features of the Study Cohort, Stratified by Axillary Staging Technique Citation Format: Giacomo Montagna, Mary Mrdutt, Astrid Botty, Andrea V. Barrio, Varadan Sevilimedu, Judy C. Boughey, Tanya L. Hoskin, Laura H. Rosenberger, E Shelley Hwang, Abigail Ingham, Bärbel Papassotiropoulos, Bich Doan Nguyen-Sträuli, Christian Kurzeder, Danilo Diaz Aybar, Denise Vorburger, Dieter Michael Matlac, Edvin Ostapenko, Fabian Riedel, Florian Fitzal, Francesco Meani, Franziska Fick, Jacqueline Sagasser, Jörg Heil, Konstantin J. Dedes, Laszlo Romics, Maggie Banys-Paluchowski, Maria Del Rosario Cueva Perez, Marcelo Chavez Diaz, Martin Heidinger, Mathias K. Fehr, Mattea Reinisch, Nadia Maggi, Nicola Rocco, Nina Ditsch, Oreste Davide Gentilini, Regis Resende Paulinelli, Sebastian Sole Zarhi, Sherko Küemmel, Simona Bruzas, Simona Di Lascio, Tamara Parissenti, Uwe Güth, Valentina Ovalle, Christoph Tausch, Monica Morrow, Thorsten Kühn, Walter P. Weber. Oncological Outcomes Following Omission of Axillary Lymph Node Dissection in Node Positive Patients Downstaging To Node Negative with Neoadjuvant Chemotherapy: the OPBC-04/EUBREAST-06/OMA study [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 GS4-02.

Background Epidemiological and self-reported data suggest that Black women may be at increased risk of developing breast cancer related lymphedema (BCRL) after axillary lymph node dissection (ALND), however prospective clinical data is lacking. BCRL risk for other racial minorities has not been well studied. We sought to evaluate the impact of race and ethnicity on BCRL incidence and severity in a prospective cohort of patients treated with ALND using defined measurement protocols. Methods Patients undergoing ALND were enrolled in a prospective BCRL screening study with arm volume (perometer) measurements and body mass index (BMI) evaluated at baseline, post-operatively, and at 6-month intervals. BCRL was defined as a relative volume change (RVC) ≥ 10% from baseline. Groups were compared using Wilcoxon rank-sum and Fischer’s exact tests. Univariate (UVA) and multivariable analysis (MVA) were used to calculate the odds ratio (OR) of developing BCRL and to compare severity of BCRL. Results From 11/2016-03/2020, 304 patients were enrolled; 268 had at least one longitudinal measurement after baseline and are included in the study. Sixty-two percent of patients were Caucasian, 21% were Black, 11% were Asian and 6% were Hispanic. Black women were older (p = 0.007), had higher baseline BMI (p < 0.001), and were more likely to be clinically node-positive (p = 0.016) compared to Caucasian, Asian and Hispanic women. Both Black and Hispanic women were more likely to undergo breast-conserving surgery (p = 0.037) and receive nodal RT (p = 0.02) (Table). At a median follow-up of 1.62 years, 50 women developed BCRL. The 18-month BCRL rate for the entire cohort was 15.9% (95%CI, 11.5% - 21.8%). Black and Hispanic women had a higher incidence of BCRL compared to Asian and Caucasian women (18-month-rate: 30.9 % [Black]; 20.2% [Hispanic] vs 10.6% [Asian]; 11.8% [Caucasian], p = 0.004). On MVA, Black race was the strongest predictor of BCRL development (Caucasian [referent]): OR 4.41, 95%CI 2.42-8.10; p < 0.001); Asian race and Hispanic ethnicity were not associated with BCRL. Other factors, including receipt of NAC (upfront surgery [referent]): OR 1.89, 95%CI 1.02-3.63; p = 0.043), older age (1.04, 95%CI 1.01-1.06; per 1-year increase), increasing number of lymph nodes removed (OR 1.05, 95%CI 1.01-1.09 per 1 additional lymph node; p = 0.007) and a longer follow-up interval (OR 1.60, 95%CI 1.31-1.96 per 6-month increase; p < 0.001) were also independently associated with BCRL development. When assessing BCRL severity, Black women were 3.85 times more likely to have a higher relative volume change compared to Caucasian women (p = 0.007), with no difference in BCRL severity identified in Hispanic and Asian women (p = NS). Conclusions In this prospective screening study, Black and Hispanic women had a higher incidence of BCRL development compared to Caucasian women, with Black race being the strongest predictor of BCRL development and of severe BCRL. Further work should address the biologic mechanisms behind racial disparities in the risk of BCRL and possible preventive strategies. Table: Clinical Characteristics of study cohort stratified by race/ethnicityOverall#(n = 268)Caucasian(n = 161)Black (n = 54)Asian(n = 29)Hispanic (n = 16)P-valueAge (years)48. (40,57)49. (40,59)50. (42,55)44. (35,52)44. (33,49)0.007Baseline BMI (kg/m2)26.2. (22.5,31.1)25.2. (22.4,30.4)29.9. (25.9,34.0)22.1. (20.6,29.1)28.1. (23.5, 32.9)< 0.001cT. 1/2. 3/4180 (67%). 88 (33%)103 (64%). 58 (36%)36 (67%). 18 (33%)25 (86%). 4 (14%)12 (75%). 4 (25%)0.5cN. 0. 1. 2/372 (27%). 173 (65%). 23 (9%)46 (29%). 102 (63%). 13 (8%)8 (15%). 45 (83%). 1 (2%)12 (41%). 14 (48%). 3 (11%)3 (19%). 9 (56%). 4 (25%)0.016Histology. Ductal. Lobular or mixed. Other220 (82%). 36 (13%). 12(4.5%)128 (80%). 25 (16%). 8 (5.0%)47 (87%). 5 (9.3%). 2 (3.7%)25 (86%). 2 (6.9%). 2 (6.9%)12 (75%). 4 (25%). 0 (0%)0.5Subtype. HR+/HER2-. HER2+. HR-/HER2-181 (68%). 51 (19%). 36 (13%)111 (69%). 34 (21%). 16 (10%)31 (57%). 9 (17%). 14 (26%)23 (79%). 4 (14%). 2 (7%)10 (62%). 4 (25%). 2 (12%)0.1Chemotherapy. Neoadjuvant. Adjuvant190 (71%). 78(29%)111 (69%). 50 (31%)42(78%). 12(22%)17(59%). 12(41%)14(88%). 2(12%)0.12Type of Surgery. BCS. Mastectomy67 (25%). 201 (75%)36 (22%). 125 (78%)19 (35%). 35 (65%)3(10%). 26 (90%)6(38%). 10 (62%)0.037Type of Reconstruction†. None. Autologous/flap. TE/implant55 (27%). 23 (11%). 123 (61%)36 (29%). 11(9%). 78 (63%)9 (26%). 8 (23%). 18 (51%)8 (31%). 2(7%). 16 (62%)1(10%). 1 (10%). 8 (80%)0.083Total number of lymph nodes removed18 (14,23)19 (14,24)17 (13,22)15 (12,23)22 (18,24)0.059Total number of positive nodes2 (1, 5)3 (1, 6)2 (1, 3)2 (1, 4)2 (1, 3)0.073Radiation therapy††252 (94%)149 (93%)54 (100%)26 (90%)16 (100%)0.070Nodal RT244 (91%)145 (90%)53 (98%)23 (79%)16 (100%)0.020BCS, breast conserving surgery; TE, tissue expander Frequency (column percent) reported for categorical variables and median (IQR) reported for continuous variables #Race/ethnicity was unknown in 8 cases †Applies to mastectomy only ††Includes any type of radiation Citation Format: Andrea V. Barrio, Giacomo Montagna, Varadan Sevilimedu, Ethan A. Gomez, Babak Mehrara, Monica Morrow. Impact of race and ethnicity on incidence and severity of breast cancer related lymphedema after axillary lymph node dissection: Results of a prospective screening study [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 GS4-01.

Background: Four prospective multi-institutional trials have demonstrated that clinically node-positive patients (cN1) who receive neoadjuvant therapy (NAC) and convert to cN0 can be reliably staged with sentinel lymph node biopsy (SLNB) with false-negative rates (FNRs) of < 10%, when ≥ 3 SLNs are retrieved. Since study patients all had axillary lymph node dissection (ALND), the rate of axillary recurrence after SLNB alone is unknown. Of concern is the possibility that residual chemotherapy-resistant axillary disease could lead to higher recurrence rates than seen in the primary surgery setting for cN0 patients where SLN FNRs of 5-10% result in axillary recurrence in < 1% of cases. Here we report regional recurrence rates in a prospectively defined cohort of cN1 patients receiving NAC, followed by a negative SLNB using a standardized technique, and no further axillary surgery. Methods: From 06/2014 to 02/2019, patients with cT1-3 biopsy-proven cN1 breast cancer who received NAC and converted to cN0 by physical exam were prospectively managed with SLNB with dual tracer mapping and omission of ALND if ≥ 3 SLNs were pathologically negative. Nodes were not routinely clipped, and retrieval of clipped metastatic nodes was not required. Pathologically negative SLNs were defined as the absence of any metastases including isolated tumor cells. Results: Of 610 cN1 patients treated with NAC, 555 (91%) converted to cN0 and had SLNB; 234 (42%) had ≥ 3 negative SLNs and were treated with SLNB alone. Median patient age was 49 years and median tumor size at presentation was 3 cm; 61% were HER2+ and 18% triple negative. Most (91%) received doxorubicin-based NAC and 88% received adjuvant radiotherapy (RT), with 80% (n = 164) of RT patients receiving nodal RT (Table). At a median follow-up of 35 months, there was only 1 (0.4%) axillary recurrence for the entire cohort, synchronous with a breast recurrence, in a patient who refused RT. Among patients who received RT (n = 205), there were no axillary recurrences. The 4-year rate of distant recurrence for all patients was 6.1% (95% CI, 3.4-10.7%) and 4-year overall survival was 93.9% (95% CI, 87.6-97.1%). Conclusion: In cN1 patients treated with NAC, rates of axillary recurrence in patients with ≥ 3 pathologically negative SLNs treated with SLNB alone were low, without routine nodal clipping. Although further follow-up is needed, multiple studies have shown that nodal recurrence is an early event, particularly in HER2+ and triple negative patients, who comprised the majority of the population. Our findings support omitting ALND in cN1 patients after NAC when the SLNs are negative using an optimal SLNB technique. Table. Patient PopulationOverall cohort (n = 234)Age, years (median, IQR)49 (40, 58)Tumor size at presentation, cm (median, IQR)3.0 (2.2, 5.0)Number SLNs retrieved (median, IQR)4 (3, 5)Palpable nodes at presentation (n, %)179 (76%)HistologyDuctal211 (90%)Lobular and mixed7 (3%)Micropapillary and mixed10 (4%)Other3 (1%)Occult3 (1%)DifferentiationWell1 (0.5%)Moderate36 (15%)Poor196 (84%)Unknown1 (0.5%)Receptor StatusHR+/HER2-47 (20%)HR+/HER2+80 (34%)HR-/HER2+64 (27%)HR-/HER2-43 (18%)Breast SurgeryBCS118 (50%)Mastectomy116 (50%)Breast pCR¥Yes161 (70%)No70 (30%)NAC regimenAC-T197 (84%)AC-T + carbo15 (6.4%)TC8 (3.4%)Other14 (6%)Neoadjuvant anti-HER2 treatmentHP (dual-therapy)144 (100%)Adjuvant RTYes205 (88%)No*29 (12%)¥3 patients had occult primary breast cancer and were not included in breast pCR calculation; *6/29 patients who did not receive RT enrolled in NSABP B-51 Citation Format: Andrea V Barrio, Giacomo Montagna, Anita Mamtani, Varadan Sevilimedu, Hiram S Cody, III, Mahmoud El-Tamer, Mary L Gemignani, Alexandra S Heerdt, Tracy-Ann Moo, Melissa Pilewskie, George Plitas, Lisa Sclafani, Kimberly J Van Zee, Monica Morrow. Axillary recurrence is a rare event in node-positive patients. treated with sentinel node biopsy alone after neoadjuvant chemotherapy: Results of a prospective study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD4-05.