Boileau, Jean-François

Abstract Background: The benefit of adjuvant regional nodal irradiation including the chest wall after mastectomy (CWI+RNI) and with whole breast irradiation (WBI+RNI) after breast conserving surgery (BCS) is well established in pts with pathologically positive axillary nodes (pN+). Pts who present with axillary node involvement (cN+), receive neoadjuvant chemotherapy (NC), and are found to be pathologically node-negative at surgery (ypN0), have lower loco-regional recurrence (LRR) rates compared to those who remain pathologically node-positive (ypN+). This phase III, randomized trial aimed to evaluate whether CWI+RNI after mastectomy or addition of RNI to WBI after BCS significantly improves invasive breast cancer recurrence-free interval (IBC-RFI) in cN+ pts found to be ypN0 after NC. Methods: Eligible pts had clinical cT1-3, N1, M0 invasive breast cancer (biopsy-proven N+ by FNA/core needle bx), completed ≥8 wks of NC (and anti-HER2 therapy if HER2+), and were ypN0 after mastectomy or BCS and sentinel node biopsy (SLNB, ≥2 nodes), axillary lymph node dissection (ALND), or both. Pts were randomized to “No RNI” (i.e., observation after mastectomy or WBI after BCS) vs. “RNI” (i.e., CWI+RNI after mastectomy or WBI+RNI after BCS). Primary endpoint was IBC-RFI. Secondary endpoints reported here: LRR-free interval (LRRFI), distant recurrence-free interval (DRFI), disease-free survival (DFS), and overall survival (OS). Study was designed to have 80% power to detect 35% reduction in annual rate of IBC-RFI for an absolute risk reduction of 4.6% (5-yr cumulative rate). Per protocol, final analysis was to occur after 172 events or 10 yrs after study initiation.Here we report the time-driven analysis prespecified in the protocol. Results: From 9/13-12/20, 1,641 pts were enrolled; 1,556 pts were available for primary event analysis; median f/u time 59.5 mos (IQR 40.7-74.1). Pt/tumor characteristics were well balanced between groups. Median age 52 yrs (range 21-84); 31% non-white; 21% cT1, 60% cT2, 19% cT3; 23% triple-negative, 21% HR+/HER2-, 56% HER2+; 58% BCS; 55% SLNB, 45% ALND+/-SLNB; and 78% had breast pathologic complete response. At the time of the analysis, 109 IBC-RFI events (63% of the planned 172) were confirmed (“No RNI”: 59, “RNI”: 50). There was no statistically significant difference between groups for IBC-RFI (HR=0.88, 95%CI 0.60-1.29; p=0.51), 5-yr point estimates: 91.8% for “No RNI” and 92.7% for “RNI.” There were no statistically significant differences between the treatment groups for secondary endpoints. There were no study-related deaths and no unexpected toxicities.Grade 4 toxicity was rare (0.1% with “No RNI”, 0.5% with “RNI”); 6.5% of pts developed grade 3 toxicity in “No RNI” and 10% in “RNI” group. Most common grade 3 toxicity was radiation dermatitis (3.3% in “No RNI,” 5.7% in “RNI”). Conclusion: In pts who present with biopsy-proven axillary node involvement and convert their axillary nodes to ypN0 after NC, CWI+RNI after mastectomy, or WBI+RNI after BCS, did not significantly improve IBC-RFI, LRRFI, DRFI, DFS, or OS. These findings suggest that downstaging involved axillary nodes with NC can result in optimization of adjuvant radiotherapy without adversely affecting oncologic outcomes. Follow-up of pts for long-term outcomes continues. NCT01872975 *EPM and JW are co-first authors. Table 1 Citation Format: Eleftherios Mamounas, Hanna Bandos, Julia White, Thomas Julian, Atif Khan, Simona Shaitelman, Mylin Torres, Frank Vicini, Patricia Ganz, Susan McCloskey, Nilendu Gupta, X. Allen Li, Peter Lucas, Nadeem Abu-Rustum, Saumil Gandhi, Rahul Tendulkar, Robert Coleman, Keiichi Fujiwara, Samantha Seaward, William Irvin, Kristin Higgins, Robert Mutter, Jean-Francois Boileau, Andrew Muskovitz, Reshma Jagsi, Anna Weiss, Curran Walter Jr., Norman Wolmark. Loco-Regional Irradiation in Patients with Biopsy-proven Axillary Node Involvement at Presentation Who Become Pathologically Node-negative After Neoadjuvant Chemotherapy: Primary Outcomes of NRG Oncology/NSABP B-51/RTOG 1304 [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 GS02-07.

ImportanceData on oncological outcomes after omission of axillary lymph node dissection (ALND) in patients with breast cancer that downstages from node positive to negative with neoadjuvant chemotherapy are sparse. Additionally, the best axillary surgical staging technique in this scenario is unknown.ObjectiveTo investigate oncological outcomes after sentinel lymph node biopsy (SLNB) with dual-tracer mapping or targeted axillary dissection (TAD), which combines SLNB with localization and retrieval of the clipped lymph node.Design, Setting, and ParticipantsIn this multicenter retrospective cohort study that was conducted at 25 centers in 11 countries, 1144 patients with consecutive stage II to III biopsy-proven node-positive breast cancer were included between April 2013 and December 2020. The cumulative incidence rates of axillary, locoregional, and any invasive (locoregional or distant) recurrence were determined by competing risk analysis.ExposureOmission of ALND after SLNB or TAD.Main Outcomes and MeasuresThe primary end points were the 3-year and 5-year rates of any axillary recurrence. Secondary end points included locoregional recurrence, any invasive (locoregional and distant) recurrence, and the number of lymph nodes removed.ResultsA total of 1144 patients (median [IQR] age, 50 [41-59] years; 78 [6.8%] Asian, 105 [9.2%] Black, 102 [8.9%] Hispanic, and 816 [71.0%] White individuals; 666 SLNB [58.2%] and 478 TAD [41.8%]) were included. A total of 1060 patients (93%) had N1 disease, 619 (54%) had ERBB2 (formerly HER2)–positive illness, and 758 (66%) had a breast pathologic complete response. TAD patients were more likely to receive nodal radiation therapy (85% vs 78%; P = .01). The clipped node was successfully retrieved in 97% of TAD cases and 86% of SLNB cases (without localization). The mean (SD) number of sentinel lymph nodes retrieved was 3 (2) vs 4 (2) (P < .001), and the mean (SD) number of total lymph nodes removed was 3.95 (1.97) vs 4.44 (2.04) (P < .001) in the TAD and SLNB groups, respectively. The 5-year rates of any axillary, locoregional, and any invasive recurrence in the entire cohort were 1.0% (95% CI, 0.49%-2.0%), 2.7% (95% CI, 1.6%-4.1%), and 10% (95% CI, 8.3%-13%), respectively. The 3-year cumulative incidence of axillary recurrence did not differ between TAD and SLNB (0.5% vs 0.8%; P = .55).Conclusions and RelevanceThe results of this cohort study showed that axillary recurrence was rare in this setting and was not significantly lower after TAD vs SLNB. These results support omission of ALND in this population.

PURPOSE The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes—both pathologic and time-to-event survival end points—particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor–positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.