Cocco, Daniela

PURPOSE The nodal burden of patients with residual isolated tumor cells (ITCs) in the sentinel lymph nodes (SLNs) after neoadjuvant chemotherapy (NAC) (ypN0i+) is unknown, and axillary management is not standardized. We investigated rates of additional positive lymph nodes (LNs) at axillary lymph node dissection (ALND) and oncologic outcomes in patients with ypN0i+ treated with and without ALND. METHODS The Oncoplastic Breast Consortium-05/ICARO cohort study (ClinicalTrials.gov identifier: NCT06464341 ) retrospectively analyzed data from patients with stage I to III breast cancer with ITCs in SLNs after NAC from 62 centers in 18 countries. The primary end point was the 3-year rate of any axillary recurrence. The rate of any invasive recurrence was the secondary end point. RESULTS In total, 583 patients were included, of whom 182 (31%) had completion ALND and 401 (69%) did not. The median age was 48 years. Most patients (74%) were clinically node-positive at diagnosis and 41% had hormone receptor–positive/human epidermal growth factor receptor 2–negative tumors. The mean number of SLNs with ITCs was 1.2. Patients treated with ALND were more likely to present with cN2/3 disease (17% v 7%, P < .001), have ITCs detected on frozen section (62% v 8%, P < .001), have lymphovascular invasion (38% v 24%, P < .001), and receive adjuvant chest wall (89% v 78%, P = .024) and nodal radiation (82% v 75%, P = .038). Additional positive nodes were found at ALND in 30% of patients, but only 5% had macrometastases. The 3-year rates of any axillary and any invasive recurrence were 2% (95% CI, 0.95 to 3.6) and 11% (95% CI, 8 to 14), respectively, with no statistical difference by type of axillary surgery. CONCLUSION The nodal burden in patients with ypN0(i+) was low, and axillary recurrence after ALND omission was rare in patients selected for this approach. These results do not support routine ALND in all patients with ypN0(i+).

Abstract Background: In patients with micro- and macrometastases in the sentinel lymph node (SLN) after neoadjuvant chemotherapy (NAC), additional positive nodes are found in &gt;60% of cases and axillary lymph node dissection (ALND) is currently considered standard of care. The likelihood of finding additional positive lymph nodes in patients with residual isolated tumor cells (ITCs) is unknown, and the benefit of ALND is unclear. As a consequence, surgical management of the axilla in these patients is not standardized. We sought to evaluate how often additional positive lymph nodes are found, to determine factors associated with ALND, and to compare oncological outcomes in patients treated with and without ALND after identification of residual ITCs in the SLN. Methods: Data were collected from 42 centers: 20 in the Oncoplastic Breast Consortium (OPBC) and EUBREAST networks, and 22 in North and South America. We included patients with cT1-4 N0-3 breast cancer at diagnosis who underwent NAC followed by axillary staging with either SLN biopsy (SLNB) or targeted axillary dissection (TAD) and were found to have residual ITCs [ypN0(i+)]. Single-tracer mapping was allowed for cN0 patients, while dual mapping or TAD was required for cN+ cases. Axillary treatment included completion ALND and/or nodal radiotherapy (RT). Competing risk analysis was performed to assess the cumulative incidence rates of any axillary recurrence (AR), locoregional recurrence (LRR), and any invasive (locoregional or distant) recurrence. Five-year cumulative incidence rates were compared between patients who underwent ALND and those who did not using the Gray’s test. Type I error rate was set to 0.05 (α). Results: We included 412 patients treated with NAC followed by surgery from 01/2009-05/2022. 146 (35.4%) had completion ALND and 266 (64.6%%) did not. Median patient age was 48 years. The majority (57%) of patients had clinical T2 tumors, and 68% had biopsy-proven N1 disease. Most were HR+/HER2- (41%) or HER2+ (39%). Most patients (80%) received anthracycline and taxane-based chemotherapy regimens. Nodal RT was administered to 83% of patients. The median number of SLNs with ITCs was 1. Patients treated with ALND were more likely to have ITCs detected on frozen section (61% v 6.7%, p&lt; 0.001), to have N2/3 disease at presentation (15.1% v 5.6%, p=0.001) and to have LVI (40% v 26%, p=0.004) (Table 1). There was no significant trend over time in the proportion of patients undergoing completion ALND during the study period (p=0.5). In the ALND group, additional positive nodes were found in 43/146 (29.5%) of cases, and consisted of macrometastases in 11/146 (7.5%), micrometastases in 9/146 (6.2%), and ITCs in 23/146 (15.8%). 5-year rates of any AR, LRR, and any invasive recurrence in the entire cohort were 2.7% (95% CI 1.2-5.4), 2.8% (95% CI 1.2-5.4) and 16% (95% CI 11-21), respectively. There was no statistical difference between patients who underwent ALND and those who did not in any of the 3 endpoints (2.2% v 3.1%, p=0.6), (2.6% v 3.0%, p=0.4) and (14% v 18%, p=0.12), respectively. Conclusion: The likelihood of finding additional positive lymph nodes in patients with ITCs after NAC is lower than in patients with residual micro- and macrometastases, and in the majority of cases, they contain ITCs. Nodal recurrence after omission of ALND is rare in this population. Overall, these results do not support routine ALND in patients with residual ITCs. Table 1. Clinicopathological Features of the Study Cohort, Stratified by Type of Axillary Surgery Frequency (row percent) reported for categorical variables, and median (IQR) reported for continuous variables. SLNB sentinel lymph node biopsy; TAD targeted axillary dissection; SLNs sentinel lymph nodes; LNs lymph nodes; pCR pathologic complete response; ACT anthracycline and taxane; AC anthracycline; H Herceptin, HP, Herceptin and Perjeta; TC taxol (or Taxotere) and carboplatinum; LVI lymphovascular invasion; BCS breast-conserving surgery. ^ Applied to HER2- tumors only (n=252). ^^ Applies to HER2+ tumors only (n=160). # LVI was present on core biopsy or final pathology. * Applies to BCS patients only (n=175). ** Applies to mastectomy patients only (n=237). Citation Format: Giacomo Montagna, Alison Laws, Massimo Ferrucci, Mary Mrdutt, Natália Polidorio, Varadan Sevilimedu, Tracy-Ann Moo, Andrea Barrio, Marissa K. Boyle, Flavia Vidal Cabero, Daniela Cocco, Fabio Corsi, Angelena Crown, Meghan R. Flanagan, Mehmet Ali Gulcelik, Callie Hlavin, Justyna Jelinska, Hasan Karanlik, Susan Kesmodel, Henry Kuerer, Sherko Küemmel, Cornelia Leo, Tehillah Menes, Melissa Pilewskie, Nina Pislar, Nicola Rocco, Jai Min Ryu, Leonardo Soares, Christoph Tausch, M. Umit Ugurlu, CICERO URBAN, Astrid Botty van de Bruele, Denise Vorburger, Fredrik Wärnberg, Anna Weiss, Austin Williams, Stephanie Wong, Steven G. Woodward, Susie X. Sun, Jennifer Q. Zhang, M. Firdos Ziauddin, Guldeniz Karadeniz Cakmak, Nuran Bese, Thorsten Kühn, Judy Boughey, Tari King, Nina Ditsch, Maggie Banys-Paluchowski, Monica Morrow, Walter Weber. Are nodal ITCs after neoadjuvant chemotherapy an indication for axillary dissection? The OPBC05/EUBREAST-14R/ICARO study [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 GS02-02.

Galvanic stimulation has long been used as a nonmechanical means of activating the vestibular apparatus through direct action on the vestibular nerve endings. This stimulation has been reported to be safe, but no studies have examined the potential changes in the corresponding cochlear receptors. The aim of the present study was to evaluate the effect of galvanic vestibular stimulation (GVS) on distortion product otoacoustic emissions (DPOAEs). Fourteen subjects underwent DPOAEs during several conditions of GVS. The DPOAEs ranged from ∼ 1 kHz to ∼ 8 kHz at 65/55 dB for f1/f2 and with an f2/f1 ratio of 1.2. The subjects were evaluated at 10 stimulation conditions that ranged from −2.0 mA to +2.0 mA for each frequency. Statistical analysis showed no significant differences in DPOAE amplitudes for all conditions with and without GVS. Results also showed no significant differences between DPOAE amplitudes before and after GVS. Multivariate analysis found subject variability in DPOAE amplitude, which was not thought to be GVS related. Results indicated that GVS produced neither temporary nor permanent changes in DPOAEs.

Abstract Background The 21-gene (Oncotype DX) Recurrence Score (RS) is a multi-gene expression assay that is both prognostic and predictive of adjuvant chemotherapy (AdjCT) benefit in estrogen receptor (ER) positive/HER2 negative breast cancer (BC). Use of the RS in TNBC and HER2+ BC is not recommended by national guidelines. Using the National Cancer Database (NCDB), we sought to evaluate whether oncologists use the RS in these subtypes. Additionally, we assessed the prognostic effects of the RS in node negative patients (pts) who did or did not receive adjuvant chemotherapy. Methods Pts with TN and HER2+ BC diagnosed from 2010-2015 in the NCDB were analyzed. Pts with neoadjuvant therapy or stage IV were excluded. Cases with RS testing were classified as low (RS 0-17), intermediate (RS 18-30) or high (RS 31+). Analysis was performed using multivariable logistic regression; overall survival (OS) was analyzed using the Kaplan-Meier method with log-rank tests. Results 142,330 pts were evaluable: 64,830 TNBC and 77,500 HER2+ (21,768 ER-/HER2+ and 55,732 ER+/HER2+). In these subtypes, RS was performed in 5,369 (3.8%) pts as follows: 1,479 (2.3%) TNBC, 185 (0.8%) ER-/HER2+, and 3,705 (6.6%) ER+/HER2+. Given the small ER-/HER2+ cohort, we focused on TNBC and ER+/HER2+. Within these subtypes, factors associated with RS testing included lower grade, smaller pathologic tumor size, pathologic N0 status, white race, age 60-69, and ILC or IMC histology (each p&lt;0.005). Of the TNBC pts tested, the RS distribution was: low 16.3%, intermediate 13.1% and high 70.6%, while for ER+/HER2+ it was low 30.5%, intermediate 30.7% and high 38.8% (p&lt;0.001). AdjCT was less frequently recommended in pts with low RS; however, this varied by tumor subtype with AdjCT recommended for 66.8% of TNBC with low RS and 37.9% of ER+/HER2+ with low RS. For intermediate RS, rates of AdjCT recommendation were 74.3% and 73.7%, and for high RS were 94.0% and 93.2% for TNBC and ER+/HER2+ respectively. In a multivariable analysis among pts with low RS, factors associated with AdjCT recommendation included younger age, larger pathologic tumor size, node positive disease, and higher grade. In AdjCT untreated TNBC, 5 yr OS did not differ for low RS (96.5%) vs intermediate RS (95.2%, p=0.82). In contrast OS was significantly worse for high RS (76.7%) than the other two groups, each p≤0.04. In AdjCT untreated ER+/HER2+, 5 yr OS was significantly better for low RS (96.7%) vs intermediate RS (92.5%, p=0.03) and vs high RS (92.1%, p=0.003), with no difference between intermediate RS vs high RS (p=0.32). Evaluating pts who did receive AdjCT, there was no significant difference in 5 yr OS for either subtype according to RS (p=0.46 and p=0.83). Interestingly, in patients with low RS, 5 yr OS was similar with or without AdjCT in both TNBC (89.5% vs 96.5%, p=0.25) and ER+/HER2+ (97.6% vs 96.7%, p=0.47). Conclusions RS testing is being conducted in a small fraction of pts with TN and HER2+ BC with lower clinical risk features. The observation that RS is prognostic for survival in AdjCT untreated patients is hypothesis generating, and suggests that further evaluation of the RS and other multigene assays in ER negative and HER2+ BC is warranted. Citation Format: Boughey JC, Hoskin TL, Cocco D, Day CN, Leon-Ferre R, Habermann EB, Goetz MP. The 21-gene recurrence score and chemotherapy use in triple negative breast cancer (TNBC) and HER2 positive breast cancer: A National Cancer Database study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-09.