NAC is commonly performed in stage II–III breast cancer patients [1, 2]. The indications for adjuvant PMRT in patients receiving NAC and mastectomy remain controversial due to a lack of prospective data. Current guidelines recommend that PMRT be performed based on the disease stage at the time of diagnosis . However, studies have shown that patients who respond well to NAC have a better prognosis regardless of clinical stage and questioned whether PMRT is necessary for these patients [14, 15, 19]. Moreover, the decision to perform PMRT is more complicated in patients with few residual lymph nodes, such as ypN1 . Without PMRT, LRR rates of 10–20% for patients with ypN1 and < 10% for those with ypN0 have been recently reported [13, 14, 21]. Therefore, the role of PMRT in patients receiving upfront systemic therapy must be evaluated in more detail. This study evaluated the treatment outcomes of patients who received NAC according to the pathologic nodal stage. We focused on identifying subgroups in which PMRT could reduce the risk of LRR.
Almost 80% of breast cancer patients show a response to NAC, as reported in National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27 . In a study based on the National Cancer Database that analyzed the response to NAC of breast cancer patients, the overall ypCR rate was 19%; the highest ypCR rate was observed in the HER2-positive subtype (38.7%), followed by the TNBC (23.2%) and luminal (8.6%) subtypes . These results are similar to those of our study, in which the ypCR rate was highest in the HER2-positive subtype, followed by the TNBC subtype. A meta-analysis of 29 prospective studies showed that ypCR after neoadjuvant treatment in breast cancer is a powerful prognostic factor . Although a tumor response is generally associated with improved survival, this relationship is most robust for the TNBC and HER2-positive subtypes . Hence, a high rate of LRR is not guaranteed when there is a residual disease after NAC. In our study, the rate of complete nodal response to modern NAC was highest in the HER2-positive subtype (63.0%, 165/262) and lowest in the luminal/HER2-negative subtype (29.4%, 91/309). However, ypN0 and ypN + patients belonging to these two subtypes showed the lowest LRR, regardless of PMRT. In other words, the benefits of PMRT may be relatively limited for the luminal/HER2-negative subtype compared to other subtypes, among patients with residual LN after NAC. Although long-term follow-up is required to evaluate the LRR in the luminal type (especially in ER + patients), the pathological nodal status after NAC alone may be insufficient to indicate the need for PMRT [26, 27].
Several studies showed that residual LNs after NAC and mastectomy are a poor prognostic factor for LRR, and PMRT appears to be associated with better survival in ypN + patients [11–13]. The current guidelines recommend adjuvant PMRT for patients with any ypN + disease, regardless of the number of residual LNs . Zhang et al. assessed LRR and DFS in 544 patients who underwent NAC and mastectomy, and demonstrated that LRR gradually increased with the number of residual LNs . Also, in the ypN1 and ypN2–3 cohorts, PMRT significantly improved LRR and DFS. However, recently, some authors insisted that PMRT can be omitted in ypN1 patients [21, 28]. Miyashita et al. reported a survival benefit of PMRT only in ypN2–3 patients, and that there was no difference in LRR, DFS, or OS according to PMRT in ypN1 patients . It has also been suggested that the neoadjuvant response index (NRI) be used for assessing the treatment response rather than binary outcomes, such as ypN + and ypN0. Using the NRI, Lee et al. showed that PMRT had little impact on the LRRFS and OS of patients who responded well to NAC (NRI of 0.7–1.0) .
In this study, PMRT conferred a survival benefit for the entire ypN + group. In the multivariate analysis, ypN2–3 patients showed significantly worse LRRFS, DFS, and OS than those with ypN1. In subgroup analysis, although PMRT was associated with a significantly improved LRR in ypN1 patients, the difference in 5-year LRRFS according to PMRT was more prominent in the ypN2–3 than ypN1 group. (48.6% vs. 13.4%, respectively; Fig. 2). These results demonstrate a difference in the response to RT between the two groups, even among patients with residual LNs after NAC. Thus, we considered it necessary to validate the effectiveness of PMRT by stratifying ypN1 patients according to the risk of LRR. Interestingly, and consistent with previous studies, there was no significant difference in LRRFS with versus without PMRT in the low-risk ypN1 patients. Therefore, in ypN1 patients, we suggest that the decision to perform PMRT should consider risk factors for LRR such as HG (HG III vs. HG I-II), LVI (present vs. absent), and molecular subtype (others vs. luminal/HER2-negative).
Several retrospective studies have evaluated whether PMRT can be omitted in ypN0 patients [14–18]. Shim et al. analyzed the effects of PMRT in 151 patients with ypN0 who underwent NAC and mastectomy; PMRT did not have a significant impact on survival outcomes . The authors also suggested that PMRT may not be necessary for pN0 patients after NAC, regardless of clinical stage. Cho et al. investigated the impact of PMRT according to molecular subtype in a study of 189 patients who achieved ypN0; PMRT did not show an additional survival benefit for any subtype . However, in a large retrospective study of 4,235 breast cancer patients who underwent NAC and total mastectomy, PMRT significantly improved LRRFS in ypT0, ypN0, and ypCR patients compared to the no-PMRT group . Given these results, whether PMRT has a survival benefit for patients without residual LN remains unclear, especially for locoregional control, compared to no-PMRT patients. The equivocal results may be partially explained by the difference in relative proportions of ypN0 molecular subtypes among the studies. In our study, neoadjuvant anti-HER2 therapy was performed in most HER2-positive patients; correspondingly, patients with HER2-overexpression accounted for a higher percentage of the ypN0 group than in previous studies.
We also showed that PMRT had no survival benefit for ypN0 patients. However, in subgroup analysis, PMRT was associated with better LRRFS compared with the no-PMRT group of ypN0 patients with the TNBC subtype. Few studies have analyzed the effects of PMRT on LRR in specific subsets of patients. However, similar to our results, several studies have reported that the TNBC subtype can increase LRR [30, 31]. Wright et al. reported that, among 464 breast cancer patients who underwent NAC and PMRT, there were 9 cases of regional recurrence, of which 7 were of the TNBC subtype. Moreover, TNBC was an independent predictor of LRR . In addition, HER2 overexpression did not emerge as a risk factor for LRR, where most patients with HER2-positive disease received neoadjuvant HER2-targeted therapy. Furthermore, Jeon et al. reported that anti-HER2 therapy improved LRR in HER2-overexpressing breast cancer patients; although this study was conducted in the adjuvant setting, it is noteworthy because it assessed the effectiveness of anti-HER2 therapy for locoregional control . The results were consistent with our findings, where the rate of LRR was lowest in the HER2-positive ypN0 patients. Therefore, we suggest that molecular subtype should be a major consideration when deciding whether to omit PMRT in ypN0 patients.
There were several limitations to our study. First, it used a retrospective design, PMRT was administered at the physician’s discretion, and there may have been selection bias. Second, the follow-up period was relatively short because we only included patients who underwent modern neoadjuvant treatment at our institution. Further studies are needed to obtain long-term follow-up data. Third, we cannot fully exclude the possibility of false-positive or -negative findings regarding nodal stage. Only 285 patients had biopsy-proven LN at diagnosis; the remaining cN + patients may have had false-positive imaging results for LNs. Additionally, the ypN0 rate was higher than in previous studies [11, 33]. The results may not only reflect the effect of modern neoadjuvant systemic treatment, but also the fact that SLNB alone was performed relatively more frequently than in other studies, resulting in false-negative ”ypN0 status” results [14, 15, 34, 35]. Lastly, the size of some pathologic nodal stage and PMRT status subgroups was small. In particular, the number of patients in the high-risk ypN1 group was low, thus limiting the power of the analysis. However, the results for the high-risk group were less important, because we focused on the low-risk group (in which PMRT was less effective). The main strength of this study was that it included most patients who had undergone modern neoadjuvant treatment at our institution, and performed subgroup analyses according to pathologic nodal status.