NAC aims to preoperatively downstage breast as well as axillary nodal in breast cancer patients(Samiei et al. 2021). However, with the more recognization to clinical value of the response of the breast tumor or lymph node to NAC, NAC is increasingly used for early-stage breast cancer with cN0(Feng et al. 2022). Risk of axillary nodal upstaging in primary cN0 breast cancer patients receiving NAC are unknown. In the current study, we focused on the pathological nodal status of cN0 patients who were underwent surgery followed by NAC, and analyzed parameters which could be a prediction factors of axillary upstaging in this kind of patients. Among 2101 patients who were cN0 prior to NAC, there was approximately 74% of patients still maintain negative axillary lymph node and another 23% patients upstaged to ypN+. We included 13 clinical/pathological features as potential predictors. ER status, tumor histology, biological subtypes, NAC regimen, cycle of NAC treatment, and bpCR associated with axillary upstaging according to the univariate analysis.
The rate of breast and axillary response is significantly associated with biological subtypes and bpCR. TNBC and HER2 positive breast cancers can achieve axillary pCR rates greater than other types (Samiei et al. 2021; Samiei et al. 2020; Haque et al.2018). Is that parallel in upstaging? Researchers from Mayo Clinic have investigated nodal upstaging in 228 cN0 patients receiving NAC and neoadjuvant endocrine therapy and found that ER+/HER2- subtype carries higher risk for nodal upstaging rather than other subtypes (Hammond et al. 2022). In our study, biological tumor subtype is an influencing factor of nodal upstaging in univariate analysis but not independent predictor. As it showed in histogram (Fig. 1), HR+/HER2- subtype appears more risk of axillary upstaging than TNBC and HER2 positive subtypes. HER2 status is not predict nodal upstaging in our study, and we ascribed it to that among those with HER2 + tumors, only nearly half underwent molecular targeted treatment because targeted drugs were not covered by medical insurance in the early years. Moreover, it had been confirmed before that the response of patients with HR positive disease to NAC was relatively low(Lopez-Tarruella et al. 2022) but we find that HR positive status is not the indicator of nodal upstaging but ER is. Among patients who achieved bpCR the rate of axillary upstaging was 8.4%, while in the non-bpCR group, it was 31.6%. In reverse, it consistent with studies that evaluating downstaging. Among 268 bpCR patients with ER-/HER2 + and TNBC subtypes there was only 14 patients upstaged to ypN + after NAC, the rate of nodal negativity was approximately 95%. Unfortunately, surgical axillary management is a routine procedure for all these patients, even it is a SLNB, patients suffer unnecessary complications like Lymphedema, paraes-thesia, arm and shoulder impairment, and pain(Verbelen et al. 2019; Gebruers et al. 2015).
A nomogram based on patients information can identify patients with very low risk of axillary disease in whom SLNB might be omitted(Moorman et al. 2022). Resent years, several nomograms have been developed to predict the axillary pathological complete response of patients who underwent NAC(Gu et al. 2022; Guo et al. 2020; Jin et al. 2016; Kang et al.2022; Hwang et al. 2019), but there was few research which discussed axillary lymph node upstaging during the NAC. To the best of our knowledge, the present nomogram is the first to predict axillary lymph node upstaging in cN0 patients who received NAC that based on real world data from a large number of multicenter patients. Apart from the ER positive status and breast pCR, tumor histology, NAC regimen, and treatment cycle are involved in our predicted nomogram. As we can see, invasive lobular carcinoma get more score than other subtypes in the possibilities of axillary upstaging. Steffi et al.(2022) reported that diagnosis of ILC was associated with larger tumors, ER and PR positivity, and lower expression of HER2, and our findings are in agreement with data from those prior study. Axillary metastasis also be controlled by targeted therapy for HER2 positive disease, NAC regimen types that didn’t include targeted therapy like TAC/ AC-T/ TA, TC/TX/TP/AC get more score for axillary upstaging in the nomogram. Interestingly if a patient receive 6 cycle of NAC, the likelihood of axillary up staging is higher than those of 8 cycle, >8 cycle, 4 cycle. It may because of that in some occasion patients receive surgery after 6 cycles of NAC due to the poor response. For patients received only 4 or less cycle NAC, surgery may cut the damage in time.
Our nomogram has additional value for the selection of cN0 patients who are not good candidates for axillary de-escalation. But it still have some limitations: (1) Chi-Chang Yu et al(Yu et al. 2022) found that Lymphovascular invasion was the strongest(OR: 29.37,95%CI:7.15–120.68)independent risk predictor of axillary metastasis in cN0 patients undergoing NAC. Unfortunately, in our study we couldn’t analyze this factor because it was not included in the initial database. (2) This study used a retrospective method, which makes it prone to potential bias compared with a prospective study. (3) No external validation was set up in this study.