Sentinel Node Biopsy Alone For Breast Cancer Patients With Residual Nodal Disease After Neoadjuvant Chemotherapy
Traditionally ALND has been the standard surgical choice for patients with primary breast cancer or node-positive disease after NAC. Because ALND is associated with a significant risk of well-known complications such as lymphedema and peripheral neurologic sequelae, there has been a trend toward less extensive axillary surgery . SLNB has replaced axillary evaluations for patients with primary breast cancer who have clinically negative nodes5. Several recent trials have provided evidence for further limiting the indication of ALND. The results of the ACOSOG Z0011 and the IBCSG 23–01 trials show that ALND is not needed in women with early stage breast cancer with limited axillary nodal burden2,6.
However, more evidence is needed to validate a reduction in the extent of axillary surgery for SLNB in patients who are clinically node-positive and have been treated with neoadjuvant chemotherapy. An important issue regarding the use of SLNB only instead of ALND is the reliability of the procedure and its results. Initial concerns about the feasibility of sentinel lymph node biopsy following neoadjuvant chemotherapy have been based on potentially altered lymphatic drainage after chemotherapy and possible nonuniform response of tumor burden from the treatment7. The false-negative rate has been a major issue, especially for patients with clinically node-positive disease. The ACOSOG Z1071 clinical trial showed that the false-negative rate of SLNB after NAC in patients with cN1 and at least 2 sentinel nodes identified during surgery was 12.6%8. Among the 343 patients who had undergone both SLNB and ALND, the overall false-negative rate was 10.7%, with no significant difference according to pretreatment node status (p = 0.51)9. Another study on the reliability of SLNB following neoadjuvant chemotherapy revealed a false-negative rate of 13% and a sentinel lymph node identification rate of 91%10. However, according to the SENTINA study, the false-negative rate was 7% or less when three or more sentinel nodes were removed, compared to 19% with two nodes removed and 24% when only one node removed11. In the present study, the mean number of the harvested sentinel lymph nodes was 4.20 for the SLNB only group and 4.26 for the ALND group. Also, because the majority of both groups had three or more axillary nodes removed (92.5% vs 90.0%), SLNB could be considered reliable based on the prior research results.
Several trials have been trying to prove the feasibility of omitting ALND for patients with limited axillary tumor burden, especially for ypN0 cases following neoadjuvant chemotherapy. There has been increasing acceptance of omitting ALND following neoadjuvant chemotherapy in patients with cN1 disease who have been found to have a negative SLNB. According to Caudle et al., 55.9% of surgeons who are familiar with the ACOSOGZ1071, SENTINA, and SN-FNAC trials are currently offering SLNB to > 50% of their patients with planned omission of ALND if SLNB is negative even though they are initially node-positive3.Kang et al. Reviewed 1,247 patients who had breast cancer with clinical conversion of axillary nodes from positive to negative after neoadjuvant chemotherapy. Of these patients, 819 patients in the ALND group and 428 patients in the SLNB group had similar axillary and distant recurrence-free survival12.
Patients treated with neoadjuvant chemotherapy who are at least ypN1 at SLNB are considered to have residual nodal disease, and ALND still remains the standard of care. To the best of our knowledge, few studies have addressed the safety of SLNB only for patients with ypN1 breast cancer, especially with 1 or 2 positive lymph nodes. In the present study, the omission of ALND was not associated with an inferior outcome in both non-matched and matched analyses in terms of ARFS, DMFS, OS, and BCSS. The results showed a lack of significant differences in outcomes between the SLNB only group and the ALND group in residual nodal disease after neoadjuvant chemotherapy. A recent retrospective study of 1,617 ypN1 patients (ALND, 1,313; SLND, 304) after neoadjuvant chemotherapy reached a rather conservative conclusion13. According to their data, the SLNB group showed significantly low survival in both univariate and multivariate analyses (HR = 1.7; 95% CI = 1.3–2.2, p < 0.001), with an estimated 5-year OS of 71%, compared with 77% in the ALND group (p = 0.01). However, there are differences in subsets of patients. Over 20% of patients had three positive lymph nodes, and this group of patients were excluded in our study. Furthermore, nearly 30% of patients were in stage 3 compared with our study population of 15% after the propensity score matching. In addition, the results of their specific subset of patients were similar to those of our study. They performed a matched subgroup analysis for patients with luminal A or B tumors and residual disease in a single lymph node. The results from the SLNB only and ALND groups were equivalent in this subset of patients (HR = 1.03, 95% CI = 0.59–1.8, p = 0.91). Also, a Kaplan–Meier analysis showed similar survival rates between the two groups, with an estimated 5-year OS of 85% and 82% for SLNB only and ALND, respectively (p = 0.88). In our study, the survivals were no different either before or after matching patients. We think that we recruited eligible patients who had only 1 or 2 metastatic nodes for analysis before matching. Among a number of variables we matched for patients’ details, the number of affected nodes may be one of the most influential factor for the survivals. Also, adjuvant therapy might be effective enough to override the baseline differences for patients with residual 1–2 nodal disease after NAC.
The multivariate analysis after matching of this study, performed to clarify the factors that exhibit significant influence on the oncologic outcome, revealed that radiation therapy was involved with improved ARFS, DMFS, and BCSS. Among other factors, the pathologic node metastasis was significant only for ARFS. We recruited patients’ data with low burden axillary disease, with only 1–2 lymph node metastasis. Thus, pathologic node, the well-known prognostic factor might not be revealed to be significant for DMFS, OS and BCSS. Our data also suggested that radiation therapy is significantly related with survival, while the univariate, multivariate, and propensity score-matched data exhibited no statistical differences between the SLNB only and ALND groups. As shown in Table 5, radiotherapy treatment was correlated with a low risk of ARFS (HR = 0.10, p = 0.018), DMFS (HR = 0.26, p = 0.046), and BCSS (HR = 0.05, p = 0.032) after matching. According to Donker et al., axillary radiotherapy can be considered as an effective alternative to ALND with acceptable outcome14. While the role of post-mastectomy radiation therapy in cN1 patients is still an area of investigation, one retrospective analysis of 15,315 cases (mastectomy, 10,283; breast-conserving surgery, 5,032; both ypN0 or ypN +) from the national cancer database has addressed this issue. In a subset analysis, OS was improved with post-mastectomy radiation therapy in the ypN1 subgroup (p < 0.0515. Among ongoing trials, a randomized phase III trial has been comparing ALND to axillary radiation in patients with breast cancer (cT1-3 N1) who have positive SLN after receiving neoadjuvant chemotherapy (AlllianceA011202). One arm comprises of ALND with nodal radiation (ALN level III and supraclavicular fossa) but no radiation to dissected axilla (ALN levels I–II), while the other arm is axillary radiation plus nodal irradiation (ALN levels I–III and supraclavicular fossa). These results should help clarify the role of axillary irradiation and thus the appropriate surgical choice for patients with ypN1 breast cancer.
Our study has several limitations. First, this study was retrospective in nature and was conducted at a single institution. And we admit that it is possible for the data to involve potential selection bias for eligible SLNB only group who might be good responders to preoperative chemotherapy. Because the patients’ clinical response to chemotherapy may clearly influence a surgeon’s decision whether to directly proceed to ALND or not. Hence, in order to control other confounding variables, we conducted a propensity score matching to reduce the selection bias. Also, these data were collected from 8 breast surgeons of AMC and we share same protocol about surgical approach based on the NCCN guideline, but not all surgeons had the exact same threshold to make decisions whether to perform ALND or not. Furthermore, we generally include clinically enlarged but without gamma signal, non-sentinel lymph nodes to the SLNB procedure so that the number of excised nodes for SLNB group may be relatively high. On the other hand, the fact that the data was collected from surgeons of diverse opinion on the axillary surgery may be a partial reflection on the actual clinical practice. Because, in the real clinical practice, each surgeon has his or her own perspective and threshold for axillary surgery. Finally, in the absence of randomized controlled trials about this issue, we believe our study might be an addition of supporting evidence for reducing axillary surgery extent while minimizing ALND-associated morbidity and preserving patients’ quality of life.
In conclusion, omission of ALND for 1 or 2 positive sentinel lymph nodes after neoadjuvant chemotherapy may not compromise locoregional control or survival. The results of this study demonstrated that the ALND-associated morbidity might be avoided without decreasing cancer control in patients with limited nodal burden after neoadjuvant chemotherapy. However, final treatment decisions should always be made in the context of a multidisciplinary setting to maximize regional control and minimize treatment related morbidity (Supplementary Information).
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