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Regional nodal irradiation (RNI) in breast cancer patients with residual isolated tumor cells or micrometastatic nodal disease after neoadjuvant chemotherapy

Open AccessPublished:November 22, 2022DOI:https://doi.org/10.1016/j.ctro.2022.11.014

      Highlights

      • Using the NCDB, we investigated the role of adjuvant regional nodal irradiation (RNI) in clinically node-positive (cN1) invasive breast cancer with residual nodal micrometastases (ypN1mi) or ITC (ypN0i+) following neoadjuvant chemotherapy and definitive surgery.
      • We found no significant difference in overall survival with the use of regional nodal irradiation in patients with residual ITC or micrometastases.
      • There was no significant difference in overall survival difference between residual micrometastases and isolated tumor cells.

      Abstract

      Background/Purpose:

      The optimal management of residual micrometastases and isolated tumor cells (ITC) in patients with invasive breast cancer who undergo neoadjuvant chemotherapy (NAC) followed by definitive surgery is not well-studied. We evaluated the role of regional nodal irradiation (RNI) in clinically node-positive (cN1) breast cancer patients with residual low-volume nodal disease following NAC.

      Methods/Materials:

      We queried the National Cancer Database (NCDB) and included patients with cN1 invasive breast cancer diagnosed from 2004-2016 who were treated with NAC and definitive surgery and had residual micrometastases (ypN1mi) or ITC (ypN0i+). We used univariable (UVA) and multivariable (MVA) Cox regression analyses to determine prognostic factors and Kaplan-Meier (KM) methods to evaluate overall survival (OS). We used inverse probability treatment weighting (IPTW) to reweight data to account for confounding factors.

      Results

      Our final cohort included 1980 patients, including 527 patients with ypN0i+ disease and 1453 patients with ypN1mi disease. 1101 patients (45.0%) received RNI in the overall cohort with a higher proportion of ypN1mi patients receiving RNI (56.5%) compared to 53.1% of ypN0i+ patients. There was no significant difference in OS between ypN0i+ and ypN1mi patients. RNI had no significant effect on OS in the overall cohort using Cox MVA and KM methods. With separate subset analysis of ypN0i+ and ypN1mi patients, there was no significant effect of RNI on OS. This was confirmed with IPTW.

      Conclusions

      In a national hospital-based study of cN1 invasive breast cancer patients with residual ITC or micrometastases after NAC, RNI did not have a significant effect on OS.

      Keywords

      1. Introduction

      The role of axillary radiation therapy (RT) following neoadjuvant chemotherapy (NAC) varies depending on the response and extent of residual nodal disease [
      • Klauber-DeMore N.
      • Ollila D.W.
      • Moore D.T.
      • Livasy C.
      • Calvo B.F.
      • Kim H.J.
      • et al.
      Size of residual lymph node metastasis after neoadjuvant chemotherapy in locally advanced breast cancer patients is prognostic.
      ,
      • Rusthoven C.G.
      • Rabinovitch R.A.
      • Jones B.L.
      • Koshy M.
      • Amini A.
      • Yeh N.
      • et al.
      The impact of postmastectomy and regional nodal radiation after neoadjuvant chemotherapy for clinically lymph node-positive breast cancer: a National Cancer Database (NCDB) analysis.
      ]. Regional nodal irradiation (RNI) is commonly used in the adjuvant setting for patients with residual macro-metastatic nodal disease following NAC due to the higher rates of locoregional failure [
      • Haffty B.G.
      • McCall L.M.
      • Ballman K.V.
      • Buchholz T.A.
      • Hunt K.K.
      • Boughey J.C.
      Impact of Radiation on Locoregional Control in Women with Node-Positive Breast Cancer Treated with Neoadjuvant Chemotherapy and Axillary Lymph Node Dissection: Results from ACOSOG Z1071 Clinical Trial.
      ]. In patients with clinically node-positive breast cancer who achieve a pathologic complete response (pCR) following NAC, the role of RNI is unclear and ongoing clinical trials are evaluating whether RNI is beneficial [
      • Klauber-DeMore N.
      • Ollila D.W.
      • Moore D.T.
      • Livasy C.
      • Calvo B.F.
      • Kim H.J.
      • et al.
      Size of residual lymph node metastasis after neoadjuvant chemotherapy in locally advanced breast cancer patients is prognostic.
      ,
      • Mamounas E.P.
      • Anderson S.J.
      • Dignam J.J.
      • Bear H.D.
      • Julian T.B.
      • Geyer C.E.
      • et al.
      Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27.
      ]. The ongoing clinical trial NSABP B-51/RTOG 1304 (B51) aims to address the role of RNI in these patients with nodal pCR following NAC and potentially identify patients in whom we may safely omit RNI. Patients with residual isolated tumor cells (ITC/ypN0i+) are included in B51, but patients with residual micrometastases are not eligible and RNI is considered standard of care in these patients [
      • Mamounas E.P.
      • Bandos H.
      • White J.R.
      • Julian T.B.
      • Khan A.J.
      • Shaitelman S.F.
      • et al.
      NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).
      ]. At the present time, there is no randomized clinical evidence to guide axillary radiation for patients with residual low volume nodal disease in the axilla.
      In the upfront surgical setting, RNI is not routinely recommended for patients with ITCs or micrometastatic nodal disease, particularly in the absence of other high-risk features such as young age, lymphovascular invasion (LVI), medial tumor location, and aggressive biology such as triple negative subtype [
      • Mamtani A.
      • Patil S.
      • Stempel M.
      • Morrow M.
      Axillary Micrometastases and Isolated Tumor Cells Are Not an Indication for Post-mastectomy Radiotherapy in Stage 1 and 2 Breast Cancer.
      ,
      • Wallgren A.
      • Bonetti M.
      • Gelber R.D.
      • Goldhirsch A.
      • Castiglione-Gertsch M.
      • Holmberg S.B.
      • et al.
      Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII.
      ]. However, the presence of ITCs and micrometastases after NAC is an entirely different entity as it represents disease that did not respond to chemotherapy. Several retrospective and national cancer registry studies have conflicting findings regarding the prognostic impact of ITC and micrometastases following NAC. In a Netherlands Cancer Registry study, patients with residual ITC or micrometastatic nodal disease had a similar prognosis for disease free survival (DFS) and overall survival (OS) compared to patients with a nodal pCR [
      • van Nijnatten T.J.A.
      • Simons J.M.
      • Moossdorff M.
      • de Munck L.
      • Lobbes M.B.I.
      • van der Pol C.C.
      • et al.
      Prognosis of residual axillary disease after neoadjuvant chemotherapy in clinically node-positive breast cancer patients: isolated tumor cells and micrometastases carry a better prognosis than macrometastases.
      ]. Of note, it is unknown which patients received RNI in this study. In contrast, Wong et al. reported a greater risk for breast cancer recurrence associated with increasing residual nodal burden as well as a two-fold increased risk of death associated with residual ITC or micrometastatic nodal disease as compared to nodal pCR [
      • Wong S.M.
      • Almana N.
      • Choi J.
      • Hu J.
      • Gagnon H.
      • Natsuhara K.
      • et al.
      Prognostic Significance of Residual Axillary Nodal Micrometastases and Isolated Tumor Cells After Neoadjuvant Chemotherapy for Breast Cancer.
      ]
      In the present study, we evaluated RNI and OS in patients with clinically node positive (cN1) invasive breast cancer who underwent NAC and definitive surgery with residual ITC or micrometastatic nodal disease using the National Cancer Database (NCDB).

      2. Methods and Materials

      2.1 Patient Selection

      We used the NCDB, a national registry maintained as a joint project of the American Cancer Society and the American College of Surgeons, which captures 70% of all malignancies diagnosed annually in the United States. We queried the database for adult patients (age ≥18) with cT0-3N1M0 breast cancer diagnosed between 2004 and 2016 who received NAC followed by breast conserving surgery (BCS) or mastectomy and whose post-neoadjuvant therapy (yp) stage at time of surgery was recorded as ypN0i+, ypN0m+ (categorized with ypN0i+) or ypN1mi. Patients were divided into 2 groups: those who did not receive RNI (BCS followed by whole breast irradiation (WBI) or mastectomy followed by no radiation or chest wall (CW) only radiation) and those who received RNI (BCS followed by WBI+RNI or mastectomy followed by RT to the CW+RNI). Patients who underwent BCS without any RT were excluded. We also excluded patients with unknown values of crucial treatment variables, including breast cancer subtype (i.e., estrogen receptor (ER), progesterone receptor [

      D. Alterio et al., “Carotid blowout syndrome after reirradiation for head and neck malignancies: a comprehensive systematic review for a pragmatic multidisciplinary approach,” Crit Rev Oncol Hematol, vol. 155, p. 103088, Nov 2020, doi: 10.1016/j.critrevonc.2020.103088.

      ], and HER2 status were all unknown, or both ER and PR status were unknown), type of surgery, whether lymph nodes were examined during surgery, margin status at surgery, ypT stage, receipt of RT, and receipt of endocrine therapy (ET). Patients were also excluded if they received RT as neoadjuvant therapy, or if they received RT to a site other than the breast, CW, or regional lymph nodes.
      Patients were stratified by year of diagnosis; age; race; Charlson-Deyo comorbidity index score (CCI score); insurance status; median ZIP code income; education level; facility type and distance to healthcare facility (miles, from patient’s residence); breast cancer histology, grade, and subtype; clinical T stage; ypT stage; type of surgery; presence of LVI; receipt of RT and ET.

      2.2 Statistical Analysis

      Chi square testing was used to compare frequency distributions between categorical variables. Overall survival (OS) was calculated using Kaplan-Meier (KM) statistics. Hazard ratios (HR) were computed using a Cox proportional hazards univariable model (UVA), as well as with a Cox multivariable model (MVA) using year of diagnosis, age, CCI score, insurance and income status, tumor histology and grade, tumor subtype, clinical T stage, ypT and ypN stages, LVI, receipt of RT and ET as covariates. To account for imbalance between treatment cohorts, the analysis was repeated using a patient cohort reweighted using the inverse probability of treatment weighting (IPTW) method, adjusting for age, tumor subtype, clinical T stage, ypT stage, type of surgery, surgical margins, LVI, and receipt of ET. All analyses were performed using R statistical software and associated packages. All tests were two-sided with a threshold of p<0.05 for significance.

      3. Results

      3.1 Patient characteristics

      We included adult patients at least 18 years of age with cT0-3N1M0 breast cancer who underwent NAC followed by BCS or mastectomy and had residual ITC or micrometastases. After applying our selection criteria, our final cohort consisted of 1980 patients (Figure 1). The median age in the cohort was 50 years (range 21 to 90 years). 527 (26.6%) patients had ypN0i+ and 1453 (73.4%) patients had ypN1mi disease. 1311 patients (66.2%) were treated with mastectomy and 669 patients (33.8%) were treated with BCS. RNI was utilized in 1101 patients (55.6%) in the overall cohort, including 53.1% of ypN0i+ patients and 56.5% of ypN1mi patients. Of the mastectomy patients who did not receive RNI (N=582), 54.5% received no PMRT and 45.5% received CW only RT. 20.3% of patients had a pCR in the breast, including 21.3% in the RNI group and 19.1% in the no RNI group. There were no significant differences between the no RNI group and RNI group regarding biologic subtype with the overall cohort consisting of 43.9% hormone receptor positive, 34.4% HER2 positive, and 21.7% hormone-receptor negative. Patients who were treated with RNI were more likely to have a higher clinical T stage, higher ypT stage, shorter distance to the healthcare facility, and use of ET. Additional patient characteristics are detailed in Table 1.
      Table 1Patient characteristics
      No RNIN=879 (%)RNIN=1101 (%)p-value
      Age
      Mean50.850.0
      ≤50447 (50.9)583 (53.0)0.377
      >50432 (49.1)518 (47.0)
      Race
      White589 (67.0)731 (66.4)0.577
      Black152 (17.3)216 (19.6)
      Hispanic79 (9.0)85 (7.7)
      Asian/SoutheastAsian/Pacific Islander38 (4.3)41 (3.7)
      Other21 (2.4)28 (2.5)
      Charlson-Deyo Score
      0786 (90.6)984 (89.4)0.427
      1-383 (9.4)117 (10.6)
      Histology
      Invasive ductal carcinoma763 (86.8)932 (84.7)0.393
      Invasive lobular carcinoma43 (4.9)61 (5.5)
      Mixed ductal/lobular or other73 (8.3)108 (9.8)
      Grade
      Low (1-2)349 (39.7)439 (39.9)0.294
      High (3 or undifferentiated/anaplastic)453 (51.5)586 (53.2)
      Unknown77 (8.8)76 (6.9)
      Margins
      Negative844 (96.0)1062 (96.5)0.694
      Positive35 (4.0)39 (3.5)
      Subtype
      Hormone-receptor positive372 (42.3)497 (45.1)0.157
      Hormone-receptor negative208 (23.7)222 (20.2)
      HER2 positive299 (34.0)382 (34.7)
      Clinical Tumor Stage
      0-1165 (18.8)152 (13.8)<0.001
      2500 (56.9)568 (51.6)
      3214 (24.3)381 (34.6)
      Number of lymph nodes examined
      1-4240 (27.3)319 (29.0)0.441
      ≥5639 (72.7)782 (71.0)
      ypT Stage
      0/is168 (19.1)234 (21.3)0.048
      1-2665 (75.7)785 (71.3)
      3-446 (5.2)82 (7.4)
      ypN Stage
      0i+/0m+247 (28.1)280 (25.4)0.199
      1mi632 (71.9)821 (74.6)
      Lymphovascular Invasion
      Absent435 (49.5)534 (48.5)0.746
      Present230 (26.2)305 (27.7)
      Other/Unknown214 (24.3)262 (23.8)
      Hormone Therapy
      No343 (39.0)377 (34.2)0.032
      Yes536 (61.0)724 (65.8)
      Surgery Type
      Breast Conserving Surgery297 (33.8)372 (33.8)1.000
      Mastectomy582 (66.2)729 (66.2)
      Facility Type
      Community51 (5.8)57 (5.2)0.346
      Comprehensive Community272 (30.9)327 (29.7)
      Academic/Research269 (30.6)316 (28.7)
      Integrated Network122 (13.9)188 (17.1)
      NA165 (18.8)213 (19.3)
      Distance to Healthcare Facility (miles)
      <10414 (47.1)585 (53.1)0.009
      ≥10463 (52.7)516 (46.9)
      NA2 (0.2)0 (0.0)
      Insurance
      Not insured17 (1.9)47 (4.3)0.005
      Private599 (68.1)764 (69.4)
      Medicaid130 (14.8)123 (11.2)
      Medicare117 (13.3)136 (12.4)
      Other government13 (1.5)21 (1.9)
      Unknown3 (0.3)10 (0.9)
      Income
      ≤48,000317 (36.1)385 (35.0)0.130
      >48,000559 (63.6)716 (65.0)
      NA3 (0.3)0 (0.0)
      Education
      <13536 (61.0)680 (61.8)0.147
      ≥13%340 (38.7)421 (38.2)
      NA3 (0.3)0 (0.0)
      Year of diagnosis
      2004 to 2011213 (24.2)259 (23.5)0.753
      2012 to 2016666 (75.8)842 (76.5)

      3.2 Survival analysis

      The median follow-up for the entire cohort was 36.1 months (range 3.4 to 159.9 months). On KM analysis, RNI had no significant effect on OS among patients in the entire cohort as well as in separate subset analyses of ypN0i + patients only and ypN1mi patients only (Figure 2).
      Figure thumbnail gr2
      Figure 2Kaplan-Meier curves based on receipt of regional nodal irradiation (RNI): a) Entire cohort; b) ypN0i+ patients only; c) ypN1mi+ patients only
      There was no significant association between RNI and OS on either Cox UVA or MVA. Additional predictors of worse OS on MVA included higher tumor grade, hormone-receptor negative disease, lack of breast pCR (ypT1-2 and ypT3-4), more recent year of diagnosis, and LVI. Mastectomy was trending towards significance for worse OS compared to BCS (HR 1.34 [0.99-1.82], p=0.062) on MVA. HER2-positive disease, use of ET, and higher income were associated with improved OS (Table 2).
      Table 2Univariable and Multivariable Cox proportional hazard regression model for overall survival (Without IPTW)
      UnivariableMultivariable
      HR95% Confidence Intervalp-valueHR95% Confidence Intervalp-value
      Age
      ≤50ReferenceReference
      >501.140.88-1.470.3211.010.99-1.020.520
      Race
      WhiteReference
      Black1.110.80-1.530.540
      Hispanic0.690.40-1.200.190
      Asian/SoutheastAsian/Pacific Islander0.980.48-2.000.964
      Other0.190.03-1.380.101
      Charlson-Deyo Score
      0ReferenceReference
      1-31.130.75-1.680.5601.260.83-1.910.288
      Histology
      Invasive ductal carcinomaReferenceReference
      Invasive lobular carcinoma0.880.48-1.610.6711.080.56-2.050.824
      Mixed ductal/lobular or other0.750.45-1.270.2860.820.48-1.390.454
      Grade
      Low (1-2)ReferenceReference
      High (3 or undifferentiated/anaplastic)1.821.35-2.45<0.0011.511.09-2.080.012
      Unknown1.901.19-3.020.007
      Margins
      NegativeReference
      Positive0.930.49-1.750.813
      Subtype
      Hormone-receptor positiveReferenceReference
      Hormone-receptor negative2.511.89-3.34<0.0011.180.75-1.840.473
      HER-2 positive0.670.47-0.970.0330.470.31-0.71<0.001
      Clinical Tumor Stage
      0-1ReferenceReference
      21.040.71-1.540.8340.960.64-1.430.841
      31.390.93-2.090.1091.180.77-1.810.460
      Number of lymph nodes examined
      1-4Reference
      ≥50.710.51-0.970.031
      ypT Stage
      0/isReferenceReference
      1-21.811.21-2.700.0042.221.46-3.37<0.001
      3-42.291.29-4.050.0042.661.44-4.900.002
      pN Stage
      0i+ReferenceReference
      1mi1.220.90-1.660.2021.260.92-1.730.146
      Lymphovascular Invasion
      AbsentReferenceReference
      Present1.651.22-2.220.0011.591.17-2.150.003
      Other/Unknown1.080.77-1.500.6621.050.74-1.470.794
      Surgery Type
      Breast Conserving SurgeryReferenceReference
      Mastectomy1.441.07-1.930.0161.330.98-1.810.072
      Endocrine Therapy
      NoReferenceReference
      Yes0.370.29-0.48<0.0010.410.27-0.62<0.001
      Regional Nodal Irradiation
      NoReferenceReference
      Yes1.040.81-1.350.7491.050.80-1.370.716
      Facility Type
      CommunityReference
      Comprehensive Community1.380.71-2.660.341
      Academic/Research1.190.61-2.300.613
      Integrated Network1.160.58-2.330.681
      Distance to Healthcare Facility (miles)
      <10Reference
      ≥100.960.74-1.240.75
      Insurance
      Not insuredReferenceReference
      Private0.500.27-0.930.0270.570.31-1.080.084
      Medicaid0.730.37-1.450.3680.710.36-1.430.341
      Medicare0.870.45-1.700.6900.700.33-1.470.341
      Other government1.020.38-2.750.9750.890.33-2.450.826
      Unknown0.670.15-3.050.6030.820.18-3.750.792
      Income
      ≤48,000ReferenceReference
      >48,0000.740.57-0.960.0260.700.53-0.910.008
      Education
      <13%Reference
      ≥13%1.040.80-1.360.757
      Year of diagnosis
      2004 to 2011ReferenceReference
      2012 to 20161.601.18-2.170.0021.691.24-2.290.001
      After reweighting with IPTW, KM analysis (Figure 3) and Cox MVA did not show a significant effect of RNI on OS.
      Figure thumbnail gr3
      Figure 3Kaplan-Meier curves based on receipt of regional nodal irradiation (RNI) with IPTW: a) Entire cohort; b) ypN0i+ patients only; c) ypN1mi+ patients only

      4. Discussion

      To our knowledge, our present study using a national hospital-based registry of clinically-node positive (N1) breast cancer patients is the largest study to evaluate the impact of RNI in patients with residual ITC or micrometastases following NAC. In the upfront surgical setting, ITCs and micrometastases have an overall excellent prognosis and RNI is typically not offered in the absence of other high risk features [
      • Mamtani A.
      • Patil S.
      • Stempel M.
      • Morrow M.
      Axillary Micrometastases and Isolated Tumor Cells Are Not an Indication for Post-mastectomy Radiotherapy in Stage 1 and 2 Breast Cancer.
      ,
      • Galimberti V.
      • Cole B.F.
      • Zurrida S.
      • Viale G.
      • Luini A.
      • Veronesi P.
      • et al.
      Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23–01): a phase 3 randomised controlled trial.
      ,
      • Giuliano A.E.
      • McCall L.
      • Beitsch P.
      • Whitworth P.W.
      • Blumencranz P.
      • Leitch A.M.
      • et al.
      Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial.
      ]. However, the significance of low volume residual nodal disease when detected after NAC is not as well studied. Our results show that patients who were treated with RNI were more likely to have higher clinical and pathologic T stage, but RNI utilization was similar among ypN0i+ and ypN1mi. We did not observe any detrimental or beneficial effect of RNI on OS using univariate or multivariable Cox analysis and after reweighting data with IPTW. Thus, this study demonstrates no significant effect of RNI on OS in either patients with residual ITCs or in patients with micrometastases.
      In our series, residual micrometastases were not associated with worse OS compared to residual ITC on univariable or multivariable Cox proportional hazard analysis. These findings are similar to a large combined institutional and NCDB analysis by Wong et al. who reported similar OS with residual micrometastases and ITCs in cN1 patients (5-year OS 78.3% vs 81.0%, respectively) [
      • Wong S.M.
      • Almana N.
      • Choi J.
      • Hu J.
      • Gagnon H.
      • Natsuhara K.
      • et al.
      Prognostic Significance of Residual Axillary Nodal Micrometastases and Isolated Tumor Cells After Neoadjuvant Chemotherapy for Breast Cancer.
      ]. Additionally, the authors also reported higher 5-year OS in patients who had a nodal pCR, but worse OS in those with residual macrometastatic nodal disease (5-year OS: ypN0 86.7%, ypN1 77.3%, ypN2-3 60.6%). In another study by van Nijnatten et al., 5-year DFS and OS were similar among ypN0 and ypN0i+/ypN1mi patients, but was significantly worse in patients with ypN1-3 disease; however, the investigators did not compare the outcomes for patients with ypN0 to ypN1mi [
      • van Nijnatten T.J.A.
      • Simons J.M.
      • Moossdorff M.
      • de Munck L.
      • Lobbes M.B.I.
      • van der Pol C.C.
      • et al.
      Prognosis of residual axillary disease after neoadjuvant chemotherapy in clinically node-positive breast cancer patients: isolated tumor cells and micrometastases carry a better prognosis than macrometastases.
      ]. When assessing the effect of RNI based on extent of residual low volume nodal disease, we also found no significant effect on OS in both ypN0i+ and ypN1mi patients. The similarities of outcomes associated with RNI among patients with ITC and micrometastases suggest that these patients may have an overall similar prognosis to patients with a nodal pCR, which can be an important decision-making factor in determining the need for adjuvant therapy.
      The surgical management of the axilla in patients with breast cancer who received NAC is an important aspect of the care and outcomes of these patients. The false negative rate in detecting positive lymph nodes is higher following NAC [
      • Cavalcante F.P.
      • Millen E.C.
      • Zerwes F.P.
      • Novita G.G.
      Role of Axillary Surgery After Neoadjuvant Chemotherapy.
      ]. Three prospective trials (ACOSOG-Z1071, SENTINA, and SN FNAC) investigated patients with clinically positive lymph nodes prior to NAC who experienced a clinical CR and underwent sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND). These trials reported an overall false-negative rate of 12.6%, 14.2%, and 13.3%, respectively, which exceed the 10% acceptable rate considered to be safe [
      • Boughey J.C.
      • et al.
      Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial.
      ,
      • Kuehn T.
      • Bauerfeind I.
      • Fehm T.
      • Fleige B.
      • Hausschild M.
      • Helms G.
      • et al.
      Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study.
      ,
      • Boileau J.-F.
      • Poirier B.
      • Basik M.
      • Holloway C.M.B.
      • Gaboury L.
      • Sideris L.
      • et al.
      Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study.
      ]. In ACOSOG-Z1071, the false negative rate was reduced when dual mapping was used (10.8% dual agent vs. 20.3% single agent, p=0.05) and when at least 3 SLN were removed compared to ≤2 SLN (9.1% vs 21.1%, p=0.007) [
      • Boughey J.C.
      • et al.
      Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial.
      ]. Similarly, in the SENTINA and SN FNAC trials, the false negative rates were reduced to 7.3% and 4.9%, respectively, when ≥3 SLN were removed [
      • Kuehn T.
      • Bauerfeind I.
      • Fehm T.
      • Fleige B.
      • Hausschild M.
      • Helms G.
      • et al.
      Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study.
      ,
      • Boileau J.-F.
      • Poirier B.
      • Basik M.
      • Holloway C.M.B.
      • Gaboury L.
      • Sideris L.
      • et al.
      Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study.
      ]. In a meta-analysis of patients with biopsy-proven node positive breast cancer who underwent NAC, the false negative rate following SLNB was 14%, but was decreased to 11% with the use of dual mapping and 4% when ≥3 SLN were removed [

      S. R. Tee et al., “Meta-analysis of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with initial biopsy-proven node-positive breast cancer,” Br J Surg, vol. 105, no. 12, pp. 1541-1552, Nov 2018, doi: 10.1002/bjs.10986.

      ]. Regarding residual micrometastases, the ALLIANCE A011202 trial will further address if ALND is necessary in cN+ patients who convert to cN0 after NAC but are found to have positive residual nodal disease (including micrometastases) in the sentinel lymph nodes. However, this trial does not include an arm with no radiation and thus this trial will not definitively answer whether all patients with residual micrometastases after NAC benefit from RNI [

      “Comparison of Axillary Lymph Node Dissection With Axillary Radiation for Patients With Node-Positive Breast Cancer Treated With Chemotherapy,” ed: https://ClinicalTrials.gov/show/NCT01901094.

      ]. NEONOD-2 is an Italian prospective non-inferiority trial that includes clinically node positive patients who have a clinical complete nodal response following NAC and undergo SLNB only. The study investigates whether patients with residual micrometastases (ypN1mi) can avoid ALND and achieve similar recurrence and survival rates to ypN0 patients (including ypN0i+). In contrast to ALLIANCE A011202, high tangents and RNI are not permitted including axillary level I/II/III/IV, and the internal mammary chain [
      • Tinterri C.
      • Canavese G.
      • Bruzzi P.
      • Dozin B.
      NEONOD 2: Rationale and design of a multicenter non-inferiority trial to assess the effect of axillary surgery omission on the outcome of breast cancer patients presenting only micrometastasis in the sentinel lymph node after neoadjuvant chemotherapy.
      ]. The NCDB does not have specific data regarding the type and extent of axillary surgery prior to 2012, so it is difficult to evaluate the type of surgical axillary evaluation in patients included in our study. Nonetheless, at least 70% of all patients in our study had at least 5 lymph nodes surgically evaluated regardless of whether they received RNI (Table 1) and we found no significant difference in number of lymph node examined (1-4 vs. ≥5 lymph nodes) in patients who had RNI vs no RNI. For clinically node positive patients who have a clinical CR after NAC, SLNB may be adequate if ≥3 SLN are identified and/or other surgical techniques such as dual mapping is used. However, for patients who have a positive SLN following NAC (including those with residual nodal micrometastases), completion ALND is still considered the standard of care while we await the results of ALLIANCE A011202 [

      “Comparison of Axillary Lymph Node Dissection With Axillary Radiation for Patients With Node-Positive Breast Cancer Treated With Chemotherapy,” ed: https://ClinicalTrials.gov/show/NCT01901094.

      ].
      Currently, there are several active randomized clinical trials that aim to address the uncertainty regarding locoregional management following NAC. The B51 trial includes patients with a nodal pCR following NAC. These patients are randomized following lumpectomy to either WBI alone or WBI with RNI or following mastectomy to PMRT with RNI or no RT. Interestingly, patients with ITCs are included in this trial [
      • Mamounas E.P.
      • Bandos H.
      • White J.R.
      • Julian T.B.
      • Khan A.J.
      • Shaitelman S.F.
      • et al.
      NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).
      ]. If this trial demonstrates a benefit of RNI in this population, then it will provide evidence for the benefit of RNI in patients with residual ITCs after NAC as these patients are included in the trial and presumably represent some of the similar or slightly higher risk patients (vs. those with an axillary pCR) who are also likely to benefit from RNI. By extrapolation, a positive finding in B51 will likely also support the use of RNI in higher risk patients, namely those with micrometastatic or macrometastatic disease in the nodes following NAC. If the trial shows no benefit of RNI in patients with a nodal pCR and ITCs, it is unclear whether this conclusion can be extended definitively to patients with residual micrometastases. If B51 proves to be a negative trial and shows no benefit to RNI in patients with a pCR, then the question asked in our study, do patients with residual micrometastases benefit from RNI, will be crucial to study in a prospective fashion. The ALLIANCE A011202 trial can help determine whether patients with residual micrometastases detected in the sentinel lymph nodes require an ALND with nodal RT or can be treated adequately with nodal RT alone [

      “Comparison of Axillary Lymph Node Dissection With Axillary Radiation for Patients With Node-Positive Breast Cancer Treated With Chemotherapy,” ed: https://ClinicalTrials.gov/show/NCT01901094.

      ]. The NEONOD-2 will address whether similar patients treated with NAC who have a clinical CR and residual micrometastases in the sentinel lymph nodes can avoid both completion ALND and RNI while achieving similar recurrence and survival rates to ypN0 patients (including ypN0i+). This study has the least intensive axillary management (no ALND or RNI) for cN1 patients who convert to ycN0 but have residual ypN1mi or ypN0i+ [
      • Tinterri C.
      • Canavese G.
      • Bruzzi P.
      • Dozin B.
      NEONOD 2: Rationale and design of a multicenter non-inferiority trial to assess the effect of axillary surgery omission on the outcome of breast cancer patients presenting only micrometastasis in the sentinel lymph node after neoadjuvant chemotherapy.
      ].
      Our study has several limitations including its retrospective nature, the heterogeneity of data, and variations in data collection including underreporting or misclassification by different hospital sites. Regarding RNI, the NCDB reports whether regional lymph nodes were irradiated in addition to breast or chest wall, but it does not specify which specific nodal levels were included in the irradiated volume (i.e. axillary level I/II, supraclavicular, internal mammary, etc.). There is also heterogeneity in radiation treatment regarding dose, modality, fractionation, and quality that limits the generalizability of our observed results. For instance, the patients who received WBI without RNI may have received some incidental radiation to the axilla which can affect outcomes and this study is unable to capture that information. There is also a lack of information on the specific chemotherapy agents used as part of NAC which is a relevant variable. We also excluded patients with unknown values for crucial variables which introduces selection bias. Furthermore, we had a relatively short follow-up which limits the conclusions of our trial. One major limitation of our study is that our endpoint of overall survival is perhaps not the best endpoint for this patient population, as early stage invasive breast cancer patients have an excellent prognosis and the vast majority of patients usually die from non-breast cancer related causes. Locoregional control and disease-free survival would be more ideal outcomes to measure for this study as these endpoints are more sensitive than OS in understanding potential benefits of RNI and are clinically meaningful for this patient population; however, data regarding disease recurrence is unavailable in the NCDB.

      5. Conclusions

      In a large national population-based analysis of breast cancer patients who underwent NAC, we report similar overall survival among patients with residual nodal ITCs or micrometastases. We found no benefit of RNI in patients with residual ITC or micrometastases in the overall cohort as well in separate subset analyses of ypN0i+ and ypN1mi patients. We eagerly await the results of B51 which will help clarify the role of RNI in patients with a nodal pCR and ITCs. If this trial shows a benefit of RNI in patients with a pCR, then there will likely be a benefit of RNI for patients with higher burden of nodal disease after NAC such as the patients included in this study. If B51 does not support any benefit to RNI, then the need for prospective study on the role of RNI for patients with low volume nodal disease after NAC will be crucial.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements:

      Joseph K. Kim, MD – Study design, writing of manuscript, creation of tables and figures.
      Jerome K. Karp, MD PhD – Statistical analysis

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