Abstract
This cohort study using pooled data from 2 randomized clinical trials examines whether removing more lymph nodes with axillary lymph node dissection improved outcomes over sentinel lymph node biopsy when most patients received adjuvant radiation therapy or regional nodal irradiation.
The surgical approach to breast cancer continues to evolve. There is an increasing focus on avoiding axillary lymph node dissection (ALND) in favor of less aggressive sentinel lymph node biopsy (SLNB) or targeted axillary dissection to reduce lymphedema.1 Adjuvant radiation therapy (RT) after SLNB can eliminate the need for ALND among patients with low-volume axillary disease who undergo upfront surgery (pN1[sn], 1-2 nodes), even though many patients will harbor undissected residual nodes.2,3 Whether RT is sufficient for controlling chemoresidual nodal disease (ypN-positive[sn]) after neoadjuvant therapy (NACT) remains unknown. The rate of positive nonsentinel nodes is higher in ypN-positive disease ranging from 60% to 75%.3,4 Further, biological concerns about chemoresistance and radiation effectiveness leaves ALND as standard of care for these patients. Few, if any, reports have investigated whether RT can control undissected nodes in the ypN-positive(sn) setting the same way it can for low-volume pN1(sn). The Alliance A011202 trial (NCT01901094) aims to answer this question decisively. Until then, we aimed to produce hypothesis-generating results by evaluating the extent of surgery used (ALND vs SLNB) in ypN-positive disease in contemporary randomized trials.
Methods
We pooled NSABP B-405 and B-416 NACT randomized data. Focusing on patients with cN-positivity who had ypN-positive disease, we compared demographic and tumor characteristics, treatment types, and clinical cancer-specific outcomes between patients who received ALND vs SLNB for ypN-positive residual disease who largely went on to receive RT. We aimed to determine whether removing more lymph nodes with ALND improved outcomes over SLNB when most patients received RT or regional nodal irradiation (RNI). Statistical analyses used SAS (version 9.4, SAS Institute) and JMP Pro statistical software (version 16.1.0, SAS Institute). Cumulative incidence method was used for local-regional recurrence (LRR), distant metastasis (DM), and any recurrence (AR); the Kaplan-Meier method was used for overall survival (OS), breast cancer–specific survival (BCSS), and disease-free survival (DFS). Differences in OS, BCSS, and DFS were assessed with Fine-Gray and log-rank tests. Significance was defined as P ≤ .05. Analysis of the data occurred from January through June of 2023.
Results
A total of 630 patients had cN-positive, ypN-positive disease. Of these, 599 received ALND, and 31 SLNB for axillary management. The median (range) follow-up for all patients was 4.5 (range 0.5-7.1) years. Notably, there were no demographic or tumor characteristic differences (Table). Patients who underwent ALND were more likely to receive a mastectomy as breast-directed treatment (P = .002). Nearly all patients in both groups received adjuvant RT (532 ALND [89%] and 29 SLNB [94%]; P = .99), and most also expressly received RNI (401 ALND [67%] and 19 SLNB [61%]; P = .43). On analysis, there were no differences in LRR, DM, AR, BCSS, FS, or OS with SLNB or ALND (Table, Figure). Focusing on the subset of patients who expressly received RNI after either SLNB (n = 19) or ALND (n = 401), there were also no differences in outcomes (Table).
Table. Patient, Tumor, Treatment, and Outcome Measure for ALND and SLNB Alone.
| Characteristic | Patients, No. (%) | P value | |
|---|---|---|---|
| ALND (n = 599) | SLNB alone (n = 31) | ||
| Patient | |||
| Age, median (range), y | 49 (25-72) | 47 (31-62) | .20 |
| Race | |||
| Black | 76 (13) | 5 (16) | .45a |
| White | 500 (83) | 25 (77) | |
| Otherb | 15 (3) | 1 (3) | |
| Ethnicity | |||
| Hispanic | 61 (10) | 2 (6) | .76 |
| Non-Hispanic | 518 (86) | 28 (90) | |
| Tumor | |||
| Clinical tumor size, median (range), cm | 5.0 (2.0-20.0) | 4.4 (2.5-13.0) | .80 |
| Clinical node-positive | 599 (100) | 31 (100) | |
| HR | |||
| Negative | 162 (27) | 9 (29) | .84 |
| Positive | 437 (73) | 22 (71) | |
| ERBB2 | |||
| Negative | 493 (82) | 25 (81) | .81 |
| Positive | 106 (18) | 6 (19) | |
| Histologic grade | |||
| G1 | 44 (7) | 2 (6) | .09 |
| G2 | 280 (47) | 10 (32) | |
| G3 | 254 (42) | 18 (58) | |
| Unknown | 21 (4) | 1 (3) | |
| Treatment | |||
| NCAT | |||
| Yes | 599 (100) | 31 (100) | |
| B40 | |||
| T then AC | 90 (15) | 4 (13) | .82 |
| T + Bev then AC + Bev | 79 (13) | 6 (19) | |
| TC then AC | 98 (16) | 3 (10) | |
| TC + Bev then AC + Bev | 77 (13) | 4 (13) | |
| TG then AC | 76 (13) | 5 (16) | |
| TG + Bev then AC + Bev | 73 (12) | 3 (10) | |
| B41 | |||
| Trastuzumab | 39 (7) | 1 (3) | .57 |
| Lapatinib | 44 (7) | 4 (13) | |
| Trastuzumab + lapatinib | 23 (4) | 1 (3) | |
| Surgery | |||
| Lumpectomy | 209 (35) | 20 (65) | .002 |
| Mastectomy | 390 (65) | 11 (35) | |
| Adjuvant RT | |||
| Yes | 532 (89) | 29 (94) | .99 |
| No | 50 (8) | 2 (6) | |
| Unknown | 17 (3) | 0 | |
| RNI RT | |||
| Yes | 401 (67) | 19 (61) | .43 |
| No | 181 (30) | 12 (39) | |
| Unknown | 17 (3) | 0 | |
| Pathology | |||
| Surgical node-positive ypN+ | 599 (100) | 31 (100) | |
| Breast pCR | |||
| Non-pCR breast | 525 (88) | 26 (84) | .57 |
| pCR breast | 74 (12) | 5 (16) | |
| 5-y Outcomesc | |||
| LRR (95% CI) | 9 (7-11) | 12 (3-28) | .79 |
| DM (95% CI) | 31 (27-35) | 26 (12-43) | .75 |
| Any recurrence (95% CI) | 33 (29-37) | 32 (15-50) | .79 |
| BCSS (95% CI) | 78 (75-82) | 79 (62-92) | .83 |
| OS (95% CI) | 75 (71-79) | 79 (60-90) | .57 |
| DFS (95% CI) | 66 (62-71) | 71 (51-85) | .85 |
Abbreviations: AC, doxorubin and cyclophosphamide; ALND, axillary lymph node dissection; BCSS, breast cancer–specific survival; Bev, bevacizumab; DFS, disease-free survival; DM, distant metastasis; HR, hormone receptor; LRR, local-regional recurrence; NA, not applicable; NCAT, neoadjuvant chemotherapy; OS, overall survival; pCR, pathologic complete response; RNI, regional nodal irradiation; RT, radiation therapy; SLNB, sentinel lymph node biopsy; T, docetaxel; TC, docetaxel + cyclophosphamide; TG, thioguanine.
White race compared with Black race.
Included Hawaiian/Pacific, Asian, and multiracial.
When specifically looking at just those patients who received RNI after SLNB (n = 19) or ALND (n = 401) to determine whether RNI may be sufficient to control ypN-positive disease after SLNB alone, we found no difference in LRR, DM, AR, BCSS, OS, or DFS at 5 years.
Figure. Risk of Recurrence for ALND vs SLNB for ypN-Positive Disease.
Disease control outcomes did not differ after axillary lymph node dissection (ALND) vs sentinel lymph node biopsy (SLNB) alone for patients with ypN-positive disease after neoadjuvant chemotherapy. A, local-regional recurrence (LRR) rates were 9% after ALND and 12% after SLNB (P = .79). B, distant metastasis (DM) rates were 31% after ALND and 26% after SLNB (P = .75). C, Rates of , any recurrence (AR) did not differ after ALND (33%) vs SLNB (32%) (P = .79).
Discussion
In this pooled analysis, we found that SLNB may have similar outcomes as ALND when most of the patients go on to receive RT. These hypothesis-generating results are some of the first of their kind. They support the need for the Alliance trial to definitively answer the extent of axillary surgery and whether RT can control low-volume chemoresidual nodes in ypN-positive(sn) disease.
Although these results are thought provoking, there are limitations preventing any conclusions. First, the size and number of nodes removed was unavailable. Decisions to offer ALND vs SLNB may have been influenced by nodal burden serving as a major confounder. Second, the analysis was substantially small for robust comparison. Third, neither trial reported RT details. We eagerly await the outcomes of the Alliance trial for further direction and whether standards will change based on results.
Data Sharing Statement
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Supplementary Materials
Data Sharing Statement
